U.S. patent application number 12/597772 was filed with the patent office on 2010-09-02 for new heterocyclic derivatives useful for the treatment of cns disorders.
This patent application is currently assigned to UCB PHARMA, S.A.. Invention is credited to Ali Ates, Benoit Kenda, Philippe Michel, Yannick Quesnel, Laurent Turet.
Application Number | 20100222326 12/597772 |
Document ID | / |
Family ID | 38461755 |
Filed Date | 2010-09-02 |
United States Patent
Application |
20100222326 |
Kind Code |
A1 |
Kenda; Benoit ; et
al. |
September 2, 2010 |
New Heterocyclic Derivatives Useful For The Treatment of CNS
Disorders
Abstract
The present invention relates to new compounds, processes for
preparing them, pharmaceutical compositions containing them and
their use as pharmaceuticals.
Inventors: |
Kenda; Benoit; (Brussels,
BE) ; Turet; Laurent; (Hamme-Mille, BE) ;
Quesnel; Yannick; (Brussels, BE) ; Michel;
Philippe; (Brussels, BE) ; Ates; Ali;
(Brussels, BE) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE, 32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
UCB PHARMA, S.A.
Brussels
BE
|
Family ID: |
38461755 |
Appl. No.: |
12/597772 |
Filed: |
April 24, 2008 |
PCT Filed: |
April 24, 2008 |
PCT NO: |
PCT/EP08/55022 |
371 Date: |
May 4, 2010 |
Current U.S.
Class: |
514/212.07 ;
514/212.08; 514/248; 514/300; 514/309; 514/312; 514/326; 514/369;
514/376; 514/386; 514/397; 514/424; 540/485; 540/523; 544/236;
546/121; 546/139; 546/158; 546/243; 548/187; 548/229; 548/312.7;
548/324.1; 548/453; 548/543 |
Current CPC
Class: |
A61K 31/4162 20130101;
A61K 31/45 20130101; A61P 25/00 20180101; A61K 31/417 20130101;
A61P 25/22 20180101; C07D 277/68 20130101; A61K 31/428 20130101;
A61P 25/06 20180101; C07D 233/32 20130101; C07D 403/06 20130101;
A61P 9/00 20180101; C07D 495/04 20130101; A61K 31/423 20130101;
C07D 217/24 20130101; C07D 277/34 20130101; A61K 31/4704 20130101;
A61P 35/00 20180101; C07D 215/227 20130101; C07D 263/38 20130101;
C07D 417/06 20130101; C07D 277/14 20130101; A61K 31/4015 20130101;
A61K 31/421 20130101; A61P 25/24 20180101; A61K 31/426 20130101;
C07D 263/20 20130101; C07D 401/06 20130101; A61P 25/16 20180101;
C07D 263/22 20130101; A61P 9/10 20180101; C07D 471/04 20130101;
C07D 519/00 20130101; A61K 31/472 20130101; A61K 31/55 20130101;
A61K 31/407 20130101; C07D 487/04 20130101 |
Class at
Publication: |
514/212.07 ;
514/386; 514/376; 514/424; 514/369; 514/248; 514/326; 514/300;
514/212.08; 514/397; 514/309; 514/312; 548/324.1; 548/312.7;
546/121; 544/236; 548/187; 548/229; 548/543; 546/243; 540/485;
540/523; 546/158; 546/139; 548/453 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/4164 20060101 A61K031/4164; A61K 31/421
20060101 A61K031/421; A61K 31/40 20060101 A61K031/40; A61K 31/426
20060101 A61K031/426; A61K 31/5025 20060101 A61K031/5025; A61K
31/454 20060101 A61K031/454; A61K 31/437 20060101 A61K031/437; A61K
31/4178 20060101 A61K031/4178; A61K 31/4725 20060101 A61K031/4725;
A61K 31/4709 20060101 A61K031/4709; A61P 25/00 20060101 A61P025/00;
A61P 25/16 20060101 A61P025/16; A61P 25/24 20060101 A61P025/24;
A61P 25/22 20060101 A61P025/22; A61P 25/06 20060101 A61P025/06;
A61P 9/00 20060101 A61P009/00; A61P 9/10 20060101 A61P009/10; A61P
35/00 20060101 A61P035/00; C07D 233/32 20060101 C07D233/32; C07D
403/06 20060101 C07D403/06; C07D 471/04 20060101 C07D471/04; C07D
487/04 20060101 C07D487/04; C07D 263/34 20060101 C07D263/34; C07D
207/36 20060101 C07D207/36; C07D 211/76 20060101 C07D211/76; C07D
223/10 20060101 C07D223/10; C07D 223/14 20060101 C07D223/14; C07D
215/227 20060101 C07D215/227; C07D 495/04 20060101 C07D495/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 27, 2007 |
EP |
EP 07008595.6 |
Claims
1. A method of treating or preventing a disease in a human, the
method comprising administering to the human an effective amount of
a compound having the formula (I), ##STR00102## or a geometrical
isomer, an enantiomer, a diastereomer or a mixture of
diastereomers, or a pharmaceutically acceptable salt of one of the
foregoing, wherein Y is O, S or NR.sup.8; R.sup.1 is hydrogen or
C.sub.1-6 alkyl; R.sup.2 is hydrogen; R.sup.3 is
--CONR.sup.5R.sup.6, --COR.sup.7, an imidazolyl, an
imidazopyridinyl, an imidazopyridazinyl or a 1H-indol-1-yl;
R.sup.5, R.sup.6 are the same or different and are independently
selected from hydrogen and C.sub.1-6 alkyl; R.sup.7 is a C.sub.1-6
alkyl; R.sup.8 is CN or C.sub.1-6 alkylsulfonyl; A is
imidazolidin-1-yl, 1,3-oxazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl,
1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl, pyrrolidin-1-yl,
piperidin-1-yl, azepan-1-yl,
5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,
hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,
2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,
1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,
3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,
1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl, or
1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl; R.sup.4 is either R.sup.4a
or R.sup.4b depending on whether A being is a monocyclic or a
bicyclic heterocycle: when A is a monocyclic heterocyclic moiety,
R.sup.4 is R.sup.4 which is hydrogen; C.sub.1-6 alkyl optionally
substituted by halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
azido, nitrooxy or aryl; C.sub.2-6 alkenyl optionally substituted
by halogen; C.sub.2-6 alkynyl optionally substituted by halogen;
azido; alkoxycarbonylamino; arylsulfonyloxy; a substituted or
unsubstituted aryl; or a 3-8 membered substituted or unsubstituted
heterocycle; when A is a bicyclic heterocyclic moiety, R.sup.4 is
R.sup.4b, which is hydrogen; nitro; cyano; halogen; heterocycle;
amino; aryl; C.sub.1-.sub.6 alkyl optionally substituted by at
least one halogen; or C.sub.1-6 alkoxy optionally substituted by at
least one halogen; with the proviso that when A=Y is
2-oxo-piperidin-1-yl, a 2-oxo-azepan-1-yl, a
2-oxo-1,3-benzothiazol-3(2H)-yl or a 2-oxo-1,3-benzoxazol-3(2H)-yl,
R.sup.3 imidazolyl, imidazopyridinyl, imidazopyridazinyl or
1H-indol-1-yl; when A=Y is 5-oxoimidazolidin-1-yl, R.sup.1 and
R.sup.2 are hydrogen, and R.sup.3 is --CONR.sup.5R.sup.6, R.sup.5
and R.sup.6 are as above defined then R.sup.4a is not alkyl,
aralkyl or substituted aralkyl; when A=Y is 2 oxo-piperidin-1-yl or
2-oxo-azepan-1-yl, and R.sup.1, R.sup.2 and R.sup.4a are hydrogen,
then R.sup.3 is not 2-phenylimidazo[1,2-a]pyridin-3-yl; when A is
pyrrolidin-1-yl, Y is NR.sup.8. when A is pyrrolidin-1-yl,
piperidin-1-yl or azepan-1-yl, R.sup.3 is --CONR.sup.5R.sup.6 or
--COR.sup.7, Y is NR.sup.8 and R.sup.8 is CN, then R.sup.4a is not
hydrogen. wherein the disease is epilepsy, epileptogenesis, seizure
disorders, convulsions, Parkinson's disease, dyskinesia induced by
dopamine replacement therapy, tardive dyskinesia induced by
administration of neuroleptic drugs, Huntington Chorea, and other
neurological disorders including bipolar disorders, mania,
depression, anxiety, panic disorders, attention deficit
hyperactivity disorder (ADHD), migraine, trigeminal and other
neuralgia, chronic pain, neuropathic pain, cerebral ischemia,
cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus,
tremor, essential tremor, simple or complex tics, Tourette
syndrome, restless leg syndrome and other movement disorders,
neonatal cerebral haemorrhage, amyotrophic lateral sclerosis,
spasticity and degenerative diseases, subjective tinnitus, apathy
syndrome, bronchial asthma, asthmatic status and allergic
bronchitis, asthmatic syndrome, bronchial hyperreactivity and
bronchospastic syndromes, lower urinary tract disorders, as well as
allergic and vasomotor rhinitis, or rhinoconjunctivitis.
2. The method according to claim 1 wherein Y is O or S; R.sup.1 is
hydrogen or C.sub.1-6 alkyl; R.sup.2 is hydrogen; R.sup.3 is
--CONR.sup.5R.sup.6, --COR.sup.7, an imidazolyl, an
imidazopyridinyl, an imidazopyridazinyl; R.sup.5, R.sup.6 are
independently hydrogen or C.sub.1-6 alkyl; R.sup.7 is a C.sub.1-6
alkyl; A is imidazolidin-1-yl, 1,3-oxazolidin-3-yl,
2,5-dihydro-1H-pyrrol-1-yl, 1,3-thiazol-3(2H)-yl,
2-oxo-1,3-thiazolidin-3-yl, piperidin-1-yl, azepan-1-yl,
5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,
hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,
2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,
1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,
3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,
1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,
1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl; R.sup.4 is either R.sup.4a
or R.sup.4b depending on whether A being is a monocyclic or a
bicyclic heterocycle: when A is a monocyclic heterocyclic moiety,
R.sup.4 is R.sup.4 which is hydrogen; C.sub.1-6 alkyl optionally
substituted by halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
azido, nitrooxy or aryl; C.sub.2-6 alkenyl optionally substituted
by halogen; C.sub.2-6 alkynyl optionally substituted by halogen;
azido; alkoxycarbonylamino; arylsulfonyloxy; a-substituted or
unsubstituted aryl; or a 3-8 membered substituted or unsubstituted
heterocycle; when A is a bicyclic heterocyclic moiety, R.sup.4 is
R.sup.4b, which is hydrogen; nitro; cyano; halogen; heterocycle;
amino; aryl; C.sub.1-.sub.6 alkyl optionally substituted by at
least one halogen; or C.sub.1-6 alkoxy optionally substituted by at
least one halogen; with the proviso that when A=Y is
2-oxo-piperidin-1-yl, 2-oxo-azepan-1-yl,
2-oxo-1,3-benzothiazol-3(2H)-yl or 2-oxo-1,3-benzoxazol-3(2H)-yl,
R.sup.3 is imidazolyl, imidazopyridinyl or imidazopyridazinyl; when
A=Y is 5-oxoimidazolidin-1-yl, R.sup.1 and R.sup.2 are hydrogen,
and R.sup.3 is --CONR.sup.5R.sup.6, R.sup.5 and R.sup.6 are as
above defined then R.sup.4a is not alkyl, aralkyl or substituted
aralkyl; when A=Y is 2 oxo-piperidin-1-yl or 2-oxo-azepan-1-yl, and
R.sup.1, R.sup.2 and R.sup.4a are hydrogen, then R.sup.3 is not
2-phenylimidazo[1,2-a]pyridin-3-yl.
3. The method according to claim 1, wherein A=Y is ##STR00103## and
wherein X is O or S, R.sup.4a/R.sup.4b are as above defined and the
asterisks indicate the attachment sites of R.sup.4a.
4. The method according to claim 1, wherein A=Y is ##STR00104##
wherein R.sup.8 is cyano or alkylsulfonyl and R.sup.4a/R.sup.4b are
as above defined and the asterisks indicate the attachment sites of
R.sup.4a.
5. The method according to claim 1 wherein the disease is
epilepsy.
6. The method according to claim 1, wherein Y is O.
7. The method according to claim 1, wherein R.sup.1 is hydrogen,
methyl or ethyl and R.sup.2 is hydrogen.
8. The method according to claim 1, wherein R.sup.3 is
--CONH.sub.2.
9. The method according to claim 1 wherein R.sup.3 is
1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,
imidazo[1,2-a]pyridin-3-yl, an 1H-indol-1-yl or
imidazo[1,2-b]pyridazin-3-yl.
10. The method according claim 1, wherein R.sup.4a is hydrogen;
C.sub.1-6 alkyl optionally substituted by halogen; or a phenyl.
11. The method according to claim 1 wherein R.sup.4b is hydrogen,
halogen, nitro, cyano, or C.sub.1-6 alkyl optionally substituted by
halogen.
12. A compound having the formula (I-A), ##STR00105## or a
geometrical isomer, an enantiomer, a diastereomer or a mixture of
diastereomers, or a pharmaceutically acceptable salt of one of the
foregoing, wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.3
is --CONH.sub.2, imidazolyl, imidazopyridinyl, imidazopyridazinyl;
R.sup.4a is either hydrogen or aryl; with the proviso that
2-(5-oxoimidazolidin-1-yl)acetamide is excluded.
13. A compound having the formula (I-B 1 or I-B2), ##STR00106## or
a geometrical isomer, an enantiomer, a diastereomer or a mixture of
diastereomers, or a pharmaceutically acceptable salt of one of the
foregoing, wherein X is either S or O; R.sup.1 is hydrogen or
C.sub.1-6 alkyl; R.sup.3 is --CONH.sub.2, imidazolyl,
imidazopyridinyl, imidazopyridazinyl; R.sup.4a is hydrogen;
C.sub.1-6 alkyl optionally substituted by halogen or C.sub.1-4
alkoxy; aryl; or C.sub.2-6 alkenyl optionally substituted by
halogen.
14. A compound having the formula (I-B3), ##STR00107## or a
geometrical isomer, an enantiomer, a diastereomer or a mixture of
diastereomers, or a pharmaceutically acceptable salt of one of the
foregoing, wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.3
is --CONH.sub.2, imidazolyl, imidazopyridinyl, imidazopyridazinyl;
R.sup.4a is C.sub.1-6 alkyl optionally substituted by halogen or
C.sub.1-4 alkoxy; aryl; or C.sub.2-6 alkenyl optionally substituted
by halogen.
15. A compound having the formula (I-C), ##STR00108## or a
geometrical isomer, an enantiomer, a diastereomer or a mixture of
diastereomers, or a pharmaceutically acceptable salt of one of the
foregoing, wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.3
is --CONH.sub.2, imidazolyl, imidazopyridinyl, imidazopyridazinyl;
R.sup.4a is methyl, ethyl, butyl optionally substituted by halogen
or C.sub.1-4 alkoxy, an unsubstituted phenyl or a phenyl
substituted by halogen, a C.sub.1-6 alkyl optionally substituted by
halogen or a C.sub.1-4 alkoxy; or R.sup.4a is a C.sub.2-6 alkenyl
optionally substituted by halogen.
16. A compound having the formula (I-D1 or I-D2), ##STR00109## or a
geometrical isomer, an enantiomer, a diastereomer or a mixture of
diastereomers, or a pharmaceutically acceptable salt of one of the
foregoing, wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.3
is imidazolyl, imidazopyridinyl, imidazopyridazinyl or
1H-indol-1-yl; R.sup.4a is hydrogen, C.sub.1-6 alkyl optionally
substituted by halogen or C.sub.1-4 alkoxy; aryl; or C.sub.2-6
alkenyl optionally substituted by halogen, with the proviso that
when R.sup.1 and R.sup.4a are hydrogen, R.sup.3 is not
2-phenylimidazo[1,2-a]pyridin-3-yl.
17. A compound having the formula (I-F1, I-F2 or I-F3),
##STR00110## or a geometrical isomer, an enantiomer, a diastereomer
or a mixture of diastereomers, or a pharmaceutically acceptable
salt of one of the foregoing, wherein R.sup.1 is hydrogen or
C.sub.1-6 alkyl; R.sup.3 is --CONH.sub.2, imidazolyl,
imidazopyridinyl or imidazopyridazinyl; R.sup.4b is hydrogen;
halogen; nitro; cyano; C.sub.1-4 alkyl optionally substituted by
halogen; C.sub.1-4 alkoxy optionally substituted by halogen.
18. A compound having the formula (I-F4), ##STR00111## or a
geometrical isomer, an enantiomer, a diastereomer or a mixture of
diastereomers, or a pharmaceutically acceptable salt of one of the
foregoing, wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.3
is imidazolyl, imidazopyridinyl or imidazopyridazinyl; R.sup.4b is
hydrogen; halogen; nitro; cyano; C.sub.1-4 alkyl optionally
substituted by halogen; C.sub.1-4 alkoxy optionally substituted by
halogen;
19. A compound having either of the formula (I-G1, I-G2 or I-G3),
##STR00112## or a geometrical isomer, an enantiomer, a diastereomer
or a mixture of diastereomers, or a pharmaceutically acceptable
salt of one of the foregoing, wherein R.sup.1 is hydrogen or
C.sub.1-6 alkyl; R.sup.3 is --CONH.sub.2, imidazolyl,
imidazopyridinyl, imidazopyridazinyl; R.sup.4b is hydrogen;
halogen; C.sub.1-4 alkyl optionally substituted by halogen;
C.sub.1-4 alkoxy optionally substituted by halogen.
20. A compound having either of the formulae (I-H1, I-H2 or I-H3),
##STR00113## or a geometrical isomer, an enantiomer, a diastereomer
or a mixture of diastereomers, or a pharmaceutically acceptable
salt of one of the foregoing, wherein R.sup.1 is hydrogen or
C.sub.1-6 alkyl; R.sup.3 is --CONH.sub.2 or imidazolyl; R.sup.8 is
cyano or C.sub.1-6 alkylsulfonyl; R.sup.4a is hydrogen, C.sub.1-6
alkyl optionally substituted by halogen or C.sub.1-4 alkoxy; aryl;
or C.sub.2-6 alkenyl optionally substituted by halogen; with the
proviso that when R.sup.8 is CN and R.sup.3 is --CONH.sub.2, then
R.sup.4a is not hydrogen.
21. The compound according to claim 12 which is
(2S)-2-{[(benzylamino)acetyl]amino}butanamide;
(2S)-2-(3-benzyl-5-oxoimidazolidin-1-yl)butanamide;
(2S)-2-(5-oxoimidazolidin-1-yl)butanamide;
(2S)-2-[3-(4-aminophenyl)-5-oxoimidazolidin-1-yl]butanamide;
(2S)-2-(allylamino)butanamide; methyl
allyl[(1S)-1-(aminocarbonyl)propyl]carbamate;
(2S)-2-(1H-pyrrol-1-yl)butanamide; methyl
4-{[(1S)-1-(aminocarbonyl)propyl]amino}-3-phenylbutanoate;
S-(1-formylbutyl)O-methyl thiocarbonate;
2-(2,4-dioxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;
2-(4-hydroxy-2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;
1-cyanopentyl 4-methylbenzenesulfonate;
S-[cyano(phenyl)methyl]ethanethioate;
S-(1-cyanopentyl)ethanethioate; 5-butyl-1,3-thiazolidin-2-one;
5-propyl-1,3-thiazolidin-2-one;
(2S)-2-[2-thioxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide-
; 1-(hydroxymethyl)-5-phenylpiperidin-2-one;
6-fluoro-3-(hydroxymethyl)-1,3-benzoxazol-2(3H)-one;
1-(hydroxymethyl)-5-propylpiperidin-2-one;
1-(hydroxymethyl)-4-phenylpiperidin-2-one;
1-(hydroxymethyl)-4-propylpiperidin-2-one;
1-(chloromethyl)-5-phenylpiperidin-2-one;
3-(chloromethyl)-6-fluoro-1,3-benzoxazol-2(3H)-one;
1-(chloromethyl)-5-propylpiperidin-2-one;
1-(chloromethyl)-4-phenylpiperidin-2-one; ethyl 4-formylheptanoate;
ethyl 4-{[(tert-butoxycarbonyl)amino]methyl}heptanoate; ethyl
4-(aminomethyl)heptanoate hydrochloride; ethyl
3-(2-bromoethyl)hexanoate; tert-butyl
2-oxo-5-propylazepane-1-carboxylate; tert-butyl
2-oxo-5-phenylazepane-1-carboxylate; 4-propylazepan-2-one;
6-propylazepan-2-one; tert-butyl
2-oxo-4-propylazepane-1-carboxylate; tert-butyl
2-oxo-6-propylazepane-1-carboxylate; methyl
4-{2-[(tert-butoxycarbonyl)amino]ethyl}heptanoate; methyl
6-[(tert-butoxycarbonyl)amino]-4-phenylhexanoate; methyl
5-{[(tert-butoxycarbonyl)amino]methyl}octanoate; methyl
6-[(tert-butoxycarbonyl)amino]-3-propylhexanoate; methyl
4-(2-aminoethyl)heptanoate hydrochloride; methyl
6-amino-4-phenylhexanoate; methyl 5-(aminomethyl)octanoate
hydrochloride; methyl 6-amino-3-propylhexanoate hydrochloride;
methyl 4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoate;
isopropyl
4-[2-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)ethyl]-
heptanoate; isopropyl
4-phenyl-6-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)-
hexanoate; methyl
5-{[(1H-imidazol-4-ylmethyl)amino]methyl}octanoate; methyl
6-[(1H-imidazol-4-ylmethyl)amino]-3-propylhexanoate;
4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoic acid
dihydrochloride;
4-[2-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)ethyl]-
heptanoic acid dihydrochloride;
4-phenyl-6-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)-
hexanoic acid dihydrochloride;
5-{[(1H-imidazol-4-ylmethyl)amino]methyl}octanoic acid
dihydrochloride; 6-[(1H-imidazol-4-ylmethyl)amino]-3-propylhexanoic
acid dihydrochloride; di-tert-butyl(3-nitro-2-thienyl)malonate;
di-tert-butyl(3-amino-2-thienyl)malonate;
di-tert-butyl{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}malonate;
{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}acetic acid
dihydrochloride;
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methylene}amino)-2-th-
ienyl]acetic acid;
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)-2-thien-
yl]acetic acid;
ethyl{4-[(tert-butoxycarbonyl)amino]-3-thienyl}acetate;
ethyl(4-amino-3-thienyl)acetate hydrochloride;
ethyl{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate; sodium
{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate;
1-{(3-ethoxy-3-oxopropanoyl)[(1-trityl-1H-imidazol-4-yl)methyl]amino}pyri-
dinium chloride; ethyl
2-oxo-1-[(1-trityl-1H-imidazol-4-yl)methyl]-1,2-dihydropyrazolo[1,5-a]pyr-
idine-3-carboxylate-methanol (1:2);
tert-butyl(5-chloro-2-methylphenyl)acetate;
methyl(5-chloro-2-methylphenyl)acetate;
methyl[2-(bromomethyl)-5-chlorophenyl]acetate; methyl
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoate;
tert-butyl(2-chloro-6-methylphenyl)acetate;
methyl(2-chloro-6-methylphenyl)acetate;
methyl[2-(bromomethyl)-6-chlorophenyl]acetate;
1-[(1-trityl-1H-imidazol-4-yl)methyl]-3,4-dihydroquinolin-2(1H)-one;
tert-butyl
7-chloro-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate;
tert-butyl
7-chloro-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate;
3-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorophenyl)propanoic
acid;
(2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-chlorophenyl)acetic
acid; 3-[2-(aminomethyl)-5-chlorophenyl]propanoic acid
hydrochloride; [2-(2-aminoethyl)-4-chlorophenyl]acetic acid
hydrochloride;
3-[5-chloro-2-({[(1-trityl-1H-imidazol-4-yl)methyl]amino}methyl)phenyl]pr-
opanoic acid,
1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]piperidin-2-one;
1-[(2-phenyl-1H-indol-1-yl)methyl]piperidin-2-one;
[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]cyanamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]acetamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]propanamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanamide; or
N-[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]methanesu-
lfonamide.
22. A pharmaceutical composition comprising a compound according to
claim 12 or a pharmaceutically acceptable salt thereof in
combination with a pharmaceutically acceptable diluent or carrier.
Description
INTRODUCTION
[0001] The present invention relates to heterocyclic compounds,
processes for preparing them, pharmaceutical compositions
containing them and their use as pharmaceuticals.
[0002] European Patent No. 0 162 036 B1 discloses compound
(S)-.alpha.-ethyl-2-oxo-1-pyrrolidine acetamide, which is known
under the International Nonproprietary Name (INN)
Levetiracetam.
[0003] Levetiracetam, a laevorotary compound, is disclosed as a
protective agent for the treatment and prevention of hypoxic and
ischemic type aggressions of the central nervous system. This
compound is also effective in the treatment of epilepsy, a
therapeutic indication for which it has been demonstrated that its
dextrorotatory enantiomer (R)-.alpha.-ethyl-2-oxo-1-pyrrolidine
acetamide, also known from European Patent No. 0 165 919 B1,
completely lacks activity (Gower A. J. et al., Eur. J. Pharmacol.
(1992), 222, 193-203).
[0004] Belavin I. Yu. et al. (Khimiko-Farmatsevticheskii Zhurnal
(1992), 26 (9-10), 74-76) discloses
1-[1-(1H-benzimidazol-1-yl)ethyl]-2-pyrrolidinone and its
anticonvulsant activity.
[0005] WO 01/62726 discloses pyrrolidinone compounds having the
following formula:
##STR00001##
[0006] WO 2005/054188 discloses imidazole derivatives having the
following formula:
##STR00002##
[0007] The imidazole or benzimidazole is attached by a nitrogen to
the methylene linker of the pyrrolidinone.
[0008] WO 02/094787 discloses.compounds having the formula:
##STR00003##
[0009] WO 2005/118561 discloses benzoxazolone compounds of the
formula:
##STR00004##
[0010] WO 2006/128692 discloses compounds of the formula:
##STR00005##
[0011] GB-1,036,280 discloses imidazole derivatives.
[0012] U.S. Pat. No. 4,650,796 discloses
3-acylaminomethylimidazo[1,2-a]pyridine derivatives.
[0013] FR-2,320,742 as well as Pinza et al in II Farmaco-Ed
Sc.-vol. 33-fasc 2, 1977 disclose pyrrolidine acetamides.
[0014] BE-857,191 discloses
1,2,4,5-tetrahydro-3H-2-benzazepine-3-ones.
[0015] It has now surprisingly been found that certain heterocyclic
derivatives are useful in the treatment of various CNS disorders
including epilepsy.
SUMMARY OF THE INVENTION
[0016] The invention provides compounds having the formula (I)
their geometrical isomers, enantiomers, diastereoisomers and
mixtures, or a pharmaceutically acceptable salt thereof,
##STR00006##
in particular for the manufacture of a medicament for the treatment
or prevention of epilepsy, epileptogenesis, seizure disorders,
convulsions, Parkinson's disease, dyskinesia induced by dopamine
replacement therapy, tardive dyskinesia induced by administration
of neuroleptic drugs, Huntington Chorea, and other neurological
disorders including bipolar disorders, mania, depression, anxiety,
panic disorders, attention deficit hyperactivity disorder (ADHD),
migraine, trigeminal and other neuralgia, chronic pain, neuropathic
pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine
abuse, stroke, myoclonus, tremor, essential tremor, simple or
complex tics, Tourette syndrome, restless leg syndrome and other
movement disorders, neonatal cerebral haemorrhage, amyotrophic
lateral sclerosis, spasticity and degenerative diseases, subjective
tinnitus, apathy syndrome, bronchial asthma, asthmatic status and
allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity
and bronchospastic syndromes, lower urinary tract disorders, as
well as allergic and vasomotor rhinitis and
rhinoconjunctivitis.
[0017] Further aspects of the invention will become apparent from
the detailed description.
[0018] A first aspect of the invention consists in compounds having
the formula (I), their geometrical isomers, enantiomers,
diastereomers and mixtures, or a pharmaceutically acceptable salt
thereof, for the treatment or prevention of epilepsy,
epileptogenesis, seizure disorders, convulsions, Parkinson's
disease, dyskinesia induced by dopamine replacement therapy,
tardive dyskinesia induced by administration of neuroleptic drugs,
Huntington Chorea, and other neurological disorders including
bipolar disorders, mania, depression, anxiety, panic disorders,
attention deficit hyperactivity disorder (ADHD), migraine,
trigeminal and other neuralgia, chronic pain, neuropathic pain,
cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse,
stroke, myoclonus, tremor, essential tremor, simple or complex
tics, Tourette syndrome, restless leg syndrome and other movement
disorders, neonatal cerebral haemorrhage, amyotrophic lateral
sclerosis, spasticity and degenerative diseases, subjective
tinnitus, apathy syndrome, bronchial asthma, asthmatic status and
allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity
and bronchospastic syndromes, lower urinary tract disorders, as
well as allergic and vasomotor rhinitis and
rhinoconjunctivitis.
[0019] Compounds of formula (I) are as follows:
##STR00007##
[0020] wherein
[0021] Y is O, S or NR.sup.8;
[0022] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0023] R.sup.2 is hydrogen;
[0024] R.sup.3 is --CONR.sup.5R.sup.6, --COR.sup.7, an imidazolyl,
an imidazopyridinyl, an imidazopyridazinyl or a 1H-indol-1-yl;
[0025] R.sup.5, R.sup.6 are the same or different and are
independently selected from hydrogen and C.sub.1-6 alkyl;
[0026] R.sup.7 is C.sub.1-6 alkyl;
[0027] A is a monocyclic or bicyclic heterocyclic moiety selected
from the group consisting of imidazolidin-1-yl,
1,3-oxazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl,
1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl, pyrrolidin-1-yl,
piperidin-1-yl, azepan-1-yl,
5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,
hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,
2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,
1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,
3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,
1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,
1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl;
[0028] R.sup.4 is either R.sup.4a or R.sup.4b depending on whether
A being is a monocyclic or a bicyclic heterocycle: [0029] where A
is a monocyclic heterocyclic moiety, R.sup.4 is R.sup.4a which is
selected from the group consisting of hydrogen; C.sub.1-6 alkyl
optionally substituted by a substituent selected from halogen,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, azido, nitrooxy or an aryl;
C.sub.2-6 alkenyl optionally substituted by halogen; C.sub.2-6
alkynyl optionally substituted by halogen; azido;
alkoxycarbonylamino; arylsulfonyloxy; a substituted or
unsubstituted aryl; or a 3-8 membered substituted or unsubstituted
heterocycle; [0030] where A is a bicyclic heterocyclic moiety
R.sup.4 is R.sup.4b which is selected from the group comprising or
consisting of hydrogen; nitro; cyano; halogen; heterocycle; amino;
aryl; C.sub.1-6 alkyl optionally substituted by at least one
halogen; or C.sub.1-6 alkoxy optionally substituted by at least one
halogen;
[0031] R.sup.8 is cyano (CN) or C.sub.1-6
alkylsulfonyl(--SO.sub.2-alkyl);
[0032] with the proviso that: [0033] For compounds where A is
selected from a piperidin-1-yl, azepan-1-yl, a
1,3-benzothiazol-3(2H)-yl or a 1,3-benzoxazol-3(2H)-yl and Y is O
or S, R.sup.3 must be selected from an imidazolyl, an
imidazopyridinyl, an imidazopyridazinyl or a 1H-indol-1-yl. [0034]
For compounds where A is a imidazolidin-1-yl, Y is O, R.sup.1 and
R.sup.2 are hydrogen, R.sup.3 is --CONR.sup.5R.sup.6, R.sup.5 and
R.sup.6 are as above defined, then R.sup.4a may not be an alkyl,
aralkyl or substituted aralkyl. [0035] Where A is either of a
piperidin-1-yl and a azepan-1-yl and Y is O, R.sup.1, R.sup.2 and
R.sup.4a are all hydrogen, then R.sup.3 could not be a
2-phenylimidazo[1,2-a]pyridin-3-yl. [0036] where A is
pyrrolidin-1-yl, Y is NR.sup.8. [0037] where A is pyrrolidin-1-yl,
piperidin-1-yl or a azepan-1-yl, R.sup.3 is --CONR.sup.5R.sup.6 or
--COR.sup.7, Y is NR.sup.8 and R.sup.8 is CN, then R.sup.4a is
different from hydrogen.
[0038] In a specific embodiment, compounds of formula (I) are as
follows:
##STR00008##
[0039] wherein
[0040] Y is O or S; preferably Y is O.
[0041] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0042] R.sup.2 is hydrogen;
[0043] R.sup.3 is --CONR.sup.5R.sup.6, --COR.sup.7, an imidazolyl,
an imidazopyridinyl, an imidazopyridazinyl;
[0044] R.sup.5, R.sup.6 are the same or different and are
independently selected from hydrogen and C.sub.1-6 alkyl;
[0045] R.sup.7 is C.sub.1-6 alkyl;
[0046] A is a monocyclic or bicyclic heterocyclic moiety selected
from the group consisting of imidazolidin-1-yl,
1,3-oxazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl,
1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl, piperidin-1-yl,
azepan-1-yl, 5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,
hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,
2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,
1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,
3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,
1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,
1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl;
[0047] R.sup.4 is either R.sup.4a or R.sup.4b depending on whether
A being is a monocyclic or a bicyclic heterocycle: [0048] where A
is a monocyclic heterocyclic moiety, R.sup.4 is R.sup.4a which is
selected from the group consisting of hydrogen; C.sub.1-6 alkyl
optionally substituted by a substituent selected from halogen,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, azido, nitrooxy or an aryl;
C.sub.2-6 alkenyl optionally substituted by halogen; C.sub.2-6
alkynyl optionally substituted by halogen; azido;
alkoxycarbonylamino; arylsulfonyloxy; a substituted or
unsubstituted aryl; or a 3-8 membered substituted or unsubstituted
heterocycle; [0049] where A is a bicyclic heterocyclic moiety
R.sup.4 is R.sup.4b which is selected from the group comprising or
consisting of hydrogen; nitro; cyano; halogen; heterocycle; amino;
aryl; C.sub.1-6 alkyl optionally substituted by at least one
halogen; or C.sub.1-6 alkoxy optionally substituted by at least one
halogen;
[0050] with the proviso that: [0051] For compounds where A=Y is
selected from a 2-oxo-piperidin-1-yl, a 2-oxo-azepan-1-yl, a
2-oxo-1,3-benzothiazol-3(2H)-yl or a 2-oxo-1,3-benzoxazol-3(2H)-yl,
R.sup.3 must be selected from an imidazolyl, an imidazopyridinyl or
an imidazopyridazinyl. [0052] For compounds where A=Y is a
5-oxoimidazolidin-1-yl, R.sup.1 and R.sup.2 are hydrogen, R.sup.3
is --CONR.sup.5R.sup.6, R.sup.5 and R.sup.6 are as above defined,
then R.sup.4a may not be an alkyl, aralkyl or substituted aralkyl.
[0053] Where A=Y is either of a 2-oxo-piperidin-1-yl and a
2-oxo-azepan-1-yl, R.sup.1, R.sup.2 and R.sup.4a are all hydrogen,
then R.sup.3 could not be a 2-phenylimidazo[1,2-a]pyridin-3-yl.
[0054] In another specific embodiment, compounds of formula (I) are
as follows:
##STR00009##
[0055] wherein
[0056] Y is NR.sup.8;
[0057] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0058] R.sup.2 is hydrogen;
[0059] R.sup.3 is --CONR.sup.5R.sup.6, --COR.sup.7, an imidazolyl,
an imidazopyridinyl, an imidazopyridazinyl or an 1H-indol-1-yl;
[0060] R.sup.5, R.sup.6 are the same or different and are
independently selected from hydrogen and C.sub.1-6 alkyl;
[0061] R.sup.7 is C.sub.1-6 alkyl;
[0062] A is a monocyclic or bicyclic heterocyclic moiety selected
from the group consisting of imidazolidin-1-yl,
1,3-oxazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl,
1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl, pyrrolidin-1-yl,
piperidin-1-yl, azepan-1-yl,
5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,
hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,
2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,
1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,
3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,
1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,
1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl;
[0063] R.sup.4 is either R.sup.4a or R.sup.4b depending on whether
A being is a monocyclic or a bicyclic heterocycle: [0064] where A
is a monocyclic heterocyclic moiety, R.sup.4 is R.sup.4a which is
selected from the group consisting of hydrogen; C.sub.1-6 alkyl
optionally substituted by a substituent selected from halogen,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, azido, nitrooxy or an aryl;
C.sub.2-6 alkenyl optionally substituted by halogen; C.sub.2-6
alkynyl optionally substituted by halogen; azido;
alkoxycarbonylamino; arylsulfonyloxy; a substituted or
unsubstituted aryl; or a 3-8 membered substituted or unsubstituted
heterocycle; [0065] where A is a bicyclic heterocyclic moiety
R.sup.4 is R.sup.4b which is selected from the group comprising or
consisting of hydrogen; nitro; cyano; halogen; heterocycle; amino;
aryl; C.sub.1-6 alkyl optionally substituted by at least one
halogen; or C.sub.1-6 alkoxy optionally substituted by at least one
halogen;
[0066] R.sup.8 is cyano (CN) or C.sub.1-6
alkylsulfonyl(--SO.sub.2-alkyl);
[0067] with the proviso that where A is pyrrolidin-1-yl,
piperidin-1-yl or a azepan-1-yl, R.sup.3 is --CONR.sup.5R.sup.6 or
--COR.sup.7, Y is NR.sup.8 and R.sup.8 is CN, then R.sup.4a is
different from hydrogen.
[0068] In another specific embodiment, compounds of formula (I) are
as follows:
##STR00010##
[0069] wherein
[0070] Y is O, S or NR.sup.8;
[0071] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0072] R.sup.2 is hydrogen;
[0073] R.sup.3 is an 1H-indol-1-yl:
[0074] A is a monocyclic or bicyclic heterocyclic moiety selected
from the group consisting of imidazolidin-1-yl,
1,3-oxazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl,
1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl, pyrrolidin-1-yl,
piperidin-1-yl, azepan-1-yl,
5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,
hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,
2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,
1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,
3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,
1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,
1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl;
[0075] R.sup.4 is either R.sup.4a or R.sup.4b depending on whether
A being is a monocyclic or a bicyclic heterocycle: [0076] where A
is a monocyclic heterocyclic moiety, R.sup.4 is R.sup.4a which is
selected from the group consisting of hydrogen; C.sub.1-6 alkyl
optionally substituted by a substituent selected from halogen,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, azido, nitrooxy or an aryl;
C.sub.2-6 alkenyl optionally substituted by halogen; C.sub.2-6
alkynyl optionally substituted by halogen; azido;
alkoxycarbonylamino; arylsulfonyloxy; a substituted or
unsubstituted aryl; or a 3-8 membered substituted or unsubstituted
heterocycle; [0077] where A is a bicyclic heterocyclic moiety
R.sup.4 is R.sup.4b which is selected from the group comprising or
consisting of hydrogen; nitro; cyano; halogen; heterocycle; amino;
aryl; C.sub.1-6 alkyl optionally substituted by at least one
halogen; or C.sub.1-6 alkoxy optionally substituted by at least one
halogen;
[0078] R.sup.8 is cyano (CN) or C.sub.1-6
alkylsulfonyl(--SO.sub.2-alkyl);
[0079] In a specific embodiment the A=Y group is selected from the
list consisting of:
##STR00011##
[0080] wherein X is O or S, in a more specific embodiment O; in
another embodiment, X is S.
[0081] The asterisks in the above illustration indicate the
attachment sites of the substituent R.sup.4a.
[0082] In another specific embodiment the A=Y group is selected
from the list consisting of:
##STR00012##
[0083] wherein R.sup.8 is cyano (CN) or C.sub.1-6
alkylsulfonyl.
[0084] The asterisks in the above illustration indicate the
attachment sites of the substituent R.sup.4a.
[0085] The compounds of the present invention are particularly
useful for the treatment of epilepsy.
[0086] In a specific embodiment, Y is O.
[0087] In a further specific embodiment, Y is NR.sup.8.
[0088] In a specific embodiment, when R.sup.3 is
--CONR.sup.5R.sup.6 and R.sup.1 is C.sub.1-6 alkyl, the carbon atom
to which R.sup.1 and R.sup.3 are attached is preferably in the
"S"-configuration.
[0089] In a specific embodiment R.sup.1 is hydrogen, methyl, ethyl
and R.sup.2 is hydrogen.
[0090] In a specific embodiment R.sup.3 is --CONH.sub.2.
[0091] In a more specific embodiment, R.sup.3 is --CONH.sub.2 and
the carbon atom to which R.sup.3 is attached is in the
"S"-configuration.
[0092] In a further specific embodiment R.sup.3 is
1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,
imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl.
[0093] In another specific embodiment R.sup.3 is 1H-indol-1-yl.
[0094] In a specific embodiment R.sup.4a is a C.sub.1-6 alkyl which
may optionally be substituted by a halogen; or a phenyl.
[0095] In another specific embodiment R.sup.4b is hydrogen,
halogen, nitro, cyano or a C.sub.1-6 alkyl optionally substituted
by a halogen.
[0096] In still a further embodiment compounds may be used in the
treatment of the above mentioned disorders, in particular of
epilepsy, having the formula (I-E), as wells as its geometrical
isomers, enantiomers, diastereomers and mixtures, or a
pharmaceutically acceptable salt thereof,
##STR00013##
[0097] wherein
[0098] X is O or S;
[0099] R.sup.1 is hydrogen or C.sub.1-6 alkyl, in a more specific
embodiment hydrogen;
[0100] R.sup.3 is an imidazolyl, an imidazopyridinyl, an
imidazopyridazinyl;
[0101] R.sup.4b is hydrogen; nitro; cyano; halogen; C.sub.1-6 alkyl
optionally substituted by halogen; C.sub.1-6 alkoxy optionally
substituted by halogen.
[0102] A further aspect of the present invention consists in novel
compounds having the formula (I-A), their geometrical isomers,
enantiomers, diastereomers and mixtures, or a pharmaceutically
acceptable salt thereof,
##STR00014##
[0103] wherein
[0104] R.sup.1 is hydrogen or C.sub.1-6 alkyl, preferably hydrogen,
methyl or ethyl; in a more specific embodiment R.sup.1 is
ethyl.
[0105] R.sup.3 is --CONH.sub.2, an imidazolyl, an imidazopyridinyl,
an imidazopyridazinyl, preferably R.sup.3 is --CONH.sub.2.
[0106] R.sup.4a is either hydrogen or an aryl; with the proviso
that 2-(5-oxoimidazolidin-1-yl)acetamide is excluded. Preferably
R.sup.4a is an aryl, e.g. a phenyl which may be substituted
preferably by halogen, nitro, alkoxy, in particular by nitro.
[0107] In a particular embodiment, when R.sup.3 is --CONH.sub.2 and
R.sup.1 is C.sub.1-6 alkyl, the carbon atom to which R.sup.1 and
R.sup.3 are attached is preferably in the "S"-configuration.
[0108] A further aspect of the present invention consists in novel
compounds having the formula (I-B1 or I-B2), their geometrical
isomers, enantiomers, diastereomers and mixtures, or a
pharmaceutically acceptable salt thereof,
##STR00015##
[0109] wherein X in formula (I-B2) is either S or O, in a more
specific embodiment S;
[0110] R.sup.1 is hydrogen or C.sub.1-6 alkyl, preferably hydrogen,
methyl or ethyl; in a more specific embodiment R.sup.1 is
ethyl.
[0111] R.sup.3 is --CONH.sub.2, an imidazolyl, an imidazopyridinyl,
an imidazopyridazinyl; preferably R.sup.3 is --CONH.sub.2.
[0112] R.sup.4a is hydrogen; C.sub.1-6 alkyl optionally substituted
by halogen or C.sub.1-4 alkoxy; an aryl; or C.sub.2-6 alkenyl
optionally substituted by halogen. Preferably, R.sup.4a is
C.sub.1-6 alkyl optionally substituted by halogen or C.sub.2-6
alkenyl optionally substituted by halogen or an aryl. In a more
specific embodiment R.sup.4a is C.sub.1-6 alkyl optionally
substituted by halogen or aryl.
[0113] In a particular embodiment, when R.sup.3 is --CONH.sub.2 and
R.sup.1 is C.sub.1-6 alkyl, the carbon atom to which R.sup.1 and
R.sup.3 are attached is preferably in the "S"-configuration.
[0114] A further aspect of the present invention consists in novel
compounds having the formula (I-B3), their geometrical isomers,
enantiomers, diastereomers and mixtures, or a pharmaceutically
acceptable salt thereof,
##STR00016##
[0115] wherein
[0116] R.sup.1 is either hydrogen or C.sub.1-6 alkyl, preferably
hydrogen, methyl or ethyl; more preferably R.sup.1 is ethyl.
[0117] R.sup.3 is --CONH.sub.2, an imidazolyl, an imidazopyridinyl,
an imidazopyridazinyl; preferably R.sup.3 is --CONH.sub.2.
[0118] R.sup.4a is C.sub.1-6 alkyl optionally substituted by
halogen or C.sub.1-4 alkoxy; an aryl; or C.sub.2-6 alkenyl
optionally substituted by halogen. Preferably, R.sup.4a is
C.sub.1-6 alkyl optionally substituted by halogen or C.sub.2-6
alkenyl optionally substituted by halogen.
[0119] In a particular embodiment, when R.sup.3 is --CONH.sub.2 and
R.sup.1 is C.sub.1-6 alkyl, the carbon atom to which R.sup.1 and
R.sup.3 are attached is preferably in the "S"-configuration.
[0120] A further aspect of the present invention consists in novel
compounds having the formula (I-C), their geometrical isomers,
enantiomers, diastereomers and mixtures, or a pharmaceutically
acceptable salt thereof,
##STR00017##
[0121] wherein
[0122] R.sup.1 is hydrogen or C.sub.1-6 alkyl, in particular
hydrogen, methyl or ethyl.
[0123] R.sup.3 is --CONH.sub.2, an imidazolyl, an imidazopyridinyl,
an imidazopyridazinyl; in particular R.sup.3 is --CONH.sub.2
[0124] R.sup.4a is methyl, ethyl, butyl optionally substituted by
halogen or C.sub.1-4 alkoxy, an unsubstituted phenyl or a phenyl
substituted by halogen, a C.sub.1-6 alkyl optionally substituted by
halogen or a C.sub.1-4 alkoxy; or R.sup.4a is a C.sub.2-6 alkenyl
optionally substituted by halogen. Preferably, R.sup.4a is methyl,
optionally substituted by halogen, an unsubstituted phenyl or a
phenyl substituted by halogen.
[0125] In a particular embodiment, when R.sup.3 is --CONH.sub.2 and
R.sup.1 is C.sub.1-6 alkyl, the carbon atom to which R.sup.1 and
R.sup.3 are attached is preferably in the "S"-configuration.
[0126] A further aspect of the present invention consists in
compounds having the formula (I-D1 or I-D2), their geometrical
isomers, enantiomers, diastereomers and mixtures, or a
pharmaceutically acceptable salt thereof,
##STR00018##
[0127] wherein
[0128] R.sup.1 is hydrogen or C.sub.1-6 alkyl, in particular
hydrogen;
[0129] R.sup.3 is an imidazolyl, an imidazopyridinyl, an
imidazopyridazinyl or a 1H-indol-1-yl. In one embodiment, R.sup.3
is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,
imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-b]pyridazin-3-yl or
1H-indol-1-yl. In a more specific embodiment, R.sup.3 is
1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,
imidazo[1,2-a]pyridin-3-yl or 1H-indol-1-yl;
[0130] R.sup.4a is hydrogen, C.sub.1-6 alkyl optionally substituted
by halogen or C.sub.1-4 alkoxy; aryl; or C.sub.2-6 alkenyl
optionally substituted by halogen. In a specific embodiment,
R.sup.4a is C.sub.1-6 alkyl optionally substituted by halogen;
aryl; or C.sub.2-6 alkenyl optionally substituted by halogen. In a
more specific embodiment R.sup.4a is C.sub.1-6 alkyl optionally
substituted by halogen; or aryl; e.g, propyl or phenyl;
[0131] with the proviso that when R.sup.1 and R.sup.4a are
hydrogen, R.sup.3 is not 2-phenylimidazo[1,2-a]pyridin-3-yl.
[0132] A further aspect of the present invention consists in
compounds having the formula (I-F1, I-F2 or I-F3), their
geometrical isomers, enantiomers, diastereomers and mixtures, or a
pharmaceutically acceptable salt thereof,
##STR00019##
[0133] wherein
[0134] R.sup.1 is hydrogen or C.sub.1-6 alkyl, preferably hydrogen,
methyl or ethyl; more preferably, R.sup.1 is hydrogen.
[0135] R.sup.3 is --CONH.sub.2, an imidazolyl, an imidazopyridinyl
or an imidazopyridazinyl; in a more specific embodiment R.sup.3 is
--CONH.sub.2, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,
imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl.
[0136] R.sup.4b is hydrogen; halogen; nitro; cyano; C.sub.1-4 alkyl
optionally substituted by halogen; C.sub.1-4 alkoxy optionally
substituted by halogen. In a more specific embodiment R.sup.4b is
hydrogen, halogen or cyano, more specifically halogen.
[0137] In a particular embodiment, when R.sup.3 is --CONH.sub.2 and
R.sup.1 is C.sub.1-6 alkyl, the carbon atom to which R.sup.1 and
R.sup.3 are attached is preferably in the "S"-configuration.
[0138] A further aspect of the present invention consists in
compounds having the formula (I-F4), their geometrical isomers,
enantiomers, diastereomers and mixtures, or a pharmaceutically
acceptable salt thereof,
##STR00020##
[0139] wherein
[0140] R.sup.1 is hydrogen or C.sub.1-6 alkyl, preferably
hydrogen;
[0141] R.sup.3 is an imidazolyl, an imidazopyridinyl or an
imidazopyridazinyl; more specifically R.sup.3 is 1H-imidazol-1-yl,
1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl or
imidazo[1,2-b]pyridazin-3-yl. More specifically R.sup.3 is
1H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl.
[0142] R.sup.4b is hydrogen; halogen; nitro; cyano; C.sub.1-4 alkyl
optionally substituted by halogen; C.sub.1-4 alkoxy optionally
substituted by halogen; specifically R.sup.4b is hydrogen, halogen
or cyano.
[0143] In a particular embodiment, when R.sup.3 is --CONH.sub.2 and
R.sup.1 is C.sub.1-6 alkyl, the carbon atom to which R.sup.1 and
R.sup.3 are attached is preferably in the "S"-configuration.
[0144] A further aspect of the present invention consists in
compounds having either of the formula (I-G1, I-G2 or I-G3), their
geometrical isomers, enantiomers, diastereomers and mixtures, or a
pharmaceutically acceptable salt thereof,
##STR00021##
[0145] wherein
[0146] R.sup.1 is hydrogen or C.sub.1-6 alkyl; preferably
hydrogen;
[0147] R.sup.3 is --CONH.sub.2, an imidazolyl, an imidazopyridinyl,
an imidazopyridazinyl; in a more specific embodiment R.sup.3 is
--CONH.sub.2, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,
imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl. In a
even more specific embodiment R.sup.3 is an 1H-imidazol-4-yl or
imidazo[1,2-a]pyridin-3-yl;
[0148] R.sup.4b is hydrogen; halogen; C.sub.1-4 alkyl optionally
substituted by halogen; C.sub.1-4 alkoxy optionally substituted by
halogen.
[0149] In a particular embodiment, when R.sup.3 is --CONH.sub.2 and
R.sup.1 is C.sub.1-6 alkyl, the carbon atom to which R.sup.1 and
R.sup.3 are attached is preferably in the "S"-configuration.
[0150] A further aspect of the present invention consists in
compounds having either of the formula (I-H1, I-H2 or I-H3), their
geometrical isomers, enantiomers, diastereomers and mixtures, or a
pharmaceutically acceptable salt thereof,
##STR00022##
[0151] wherein
[0152] R.sup.1 is hydrogen or C.sub.1-6 alkyl; preferably hydrogen
or methyl or ethyl;
[0153] R.sup.3 is --CONH.sub.2 or an imidazolyl; preferably
--CONH.sub.2;
[0154] R.sup.8 is cyano or C.sub.1-6 alkylsulfonyl;
[0155] R.sup.4a is hydrogen, C.sub.1-6 alkyl optionally substituted
by halogen or C.sub.1-4 alkoxy; aryl; or C.sub.2-6 alkenyl
optionally substituted by halogen. In a specific embodiment,
R.sup.4a is C.sub.1-6 alkyl optionally substituted by halogen;
aryl; or C.sub.2-6 alkenyl optionally substituted by halogen. In a
more specific embodiment R.sup.4a is C.sub.1-6 alkyl optionally
substituted by halogen; or aryl; e.g, propyl;
[0156] with the proviso that where R.sup.8 is CN and R.sup.3 is
--CONH2, then R.sup.4a is not hydrogen.
[0157] In a particular embodiment, when R.sup.3 is --CONH.sub.2 and
R.sup.1 is C.sub.1-6 alkyl, the carbon atom to which R.sup.1 and
R.sup.3 are attached is preferably in the "S"-configuration.
[0158] Specific compounds of the present invention are those
selected from the group consisting of:
(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;
(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;
(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide;
2[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;
2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;
2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;
2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;
(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;
2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide;
2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide;
2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide;
2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide;
2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide;
2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;
2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;
(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;
1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piper-
idin-2-one; 1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;
1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;
1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepa-
n-2-one; 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one;
5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan--
2-one;
5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}a-
zepan-2-one; 1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one;
1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one;
4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;
2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide;
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H--
thieno[3,2-b]pyrrol-5-one;
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thi-
eno[3,2-b]pyrrol-5-one;
1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;
2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;
2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;
2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;
2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one;
1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one;
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide;
5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;
2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;
2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;
1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one;
2-(6-iodo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;
2-(6-cyano-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;
7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,-
5-tetrahydro-3H-2-benzazepin-3-one;
7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3--
one;
7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepi-
n-2-one;
7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl-
}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one;
1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]piperidin-2-one;
1-[(2-phenyl-1H-indol-1-yl)methyl]piperidin-2-one;
[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]cyanamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]acetamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]propanamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanamide; and
N-[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]methanesu-
lfonamide.
[0159] Most preferred compounds of the present invention are those
selected from the group consisting of:
1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;
1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;
1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;
6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;
2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;
5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;
1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]piperidin-2-one; and
[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]cyanamide.
[0160] The compounds of the present invention are for use as a
medicament, in particular for disorder is selected from the group
consisting of epilepsy, epileptogenesis, seizure disorders,
convulsions, Parkinson's disease, dyskinesia induced by dopamine
replacement therapy, tardive dyskinesia induced by administration
of neuroleptic drugs, Huntington Chorea, and other neurological
disorders including bipolar disorders, mania, depression, anxiety,
panic disorders, attention deficit hyperactivity disorder (ADHD),
migraine, trigeminal and other neuralgia, chronic pain, neuropathic
pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine
abuse, stroke, myoclonus, tremor, essential tremor, simple or
complex tics, Tourette syndrome, restless leg syndrome and other
movement disorders, neonatal cerebral haemorrhage, amyotrophic
lateral sclerosis, spasticity and degenerative diseases, subjective
tinnitus, apathy syndrome; bronchial asthma, asthmatic status and
allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity
and bronchospastic syndromes, lower urinary tract disorders, as
well as allergic and vasomotor rhinitis and
rhinoconjunctivitis.
[0161] Specific disorders are epilepsy, dyskinesia induced by
dopamine replacement therapy, chronic pain, neuropathic pain.
[0162] A further aspect of the present invention relates to a
pharmaceutical composition comprising an effective amount of a
compound of formula (I) in combination with a pharmaceutically
acceptable diluent or carrier.
[0163] The following paragraphs provide definitions of the various
chemical moieties that make up the compounds according to the
invention and are intended to apply uniformly through-out the
specification and claims unless an otherwise expressly set out
definition provides a broader definition.
[0164] "C.sub.1-6 alkyl" refers to alkyl groups having 1 to 6, or 1
to 4 carbon atoms. This term is exemplified by groups such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
n-pentyl, n-hexyl, trifluoromethyl and the like.
[0165] "Aryl" refers to an unsaturated aromatic carbocyclic group
of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or
multiple condensed rings (e.g., naphthyl). Preferred aryl include
phenyl, naphthyl, phenantrenyl and the like.
[0166] "Heterocycle" refers to a saturated or unsaturated ring
system containing, in addition to carbon atoms, at least one hetero
atom, such as nitrogen, oxygen and/or sulfur. "Heterocycle"
includes both "heteroaryl" and "heterocycloalkyl".
[0167] "Heteroaryl" refers to a monocyclic heteroaromatic, or a
bicyclic or a tricyclic fused-ring heteroaromatic group. Particular
examples of heteroaromatic groups include optionally substituted
pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-triazinyl,
1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl,
isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl,
indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazopyridinyl,
benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl,
pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,
pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,
quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,
xanthenyl,benzoquinolyl, imidazopyrimidinyl, imidazopyridazinyl,
imidazothiazolyl or imidazothiadiazolyl.
[0168] "C.sub.2-6 alkenyl" refers to alkenyl groups preferably
having from 2 to 6 carbon atoms and having at least 1 or 2 sites of
alkenyl unsaturation. Preferable alkenyl groups include ethenyl
(vinyl, --CH.dbd.CH.sub.2), n-2-propenyl (allyl,
--CH.sub.2CH.dbd.CH.sub.2) and the like.
[0169] "C.sub.2-6 alkynyl" refers to alkynyl groups preferably
having from 2 to 6 carbon atoms and having at least 1-2 sites of
alkynyl unsaturation, preferred alkynyl groups include
ethynyl(--C.ident.CH), propargyl(--CH.sub.2C.ident.CH), and the
like.
[0170] "C.sub.3-8 cycloalkyl" refers to a saturated carbocyclic
group of from 3 to 8 carbon atoms having a single ring (e.g.,
cyclohexyl) or multiple condensed rings (e.g., norbornyl).
[0171] Preferred cycloalkyl include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, norbornyl and the like.
[0172] "Heterocycloalkyl" refers to a C.sub.3-8 cycloalkyl group
according to the definition above, in which 1 to 3 carbon atoms are
replaced by hetero atoms chosen from the group consisting of O, S,
NR, R being defined as hydrogen or C.sub.1-6 alkyl.
[0173] "Alkoxy" refers to the group --O--R where R includes
"C.sub.1-6 alkyl", "C.sub.2-6 alkenyl", "C.sub.2-6 alkynyl",
"C.sub.3-8 cycloalkyl", "heterocycloalkyl", "aryl",
"heteroaryl".
[0174] "Amino" refers to the group --NRR' where each R, R' is
independently hydrogen, "C.sub.1-6 alkyl", "C.sub.2-6 alkenyl",
"C.sub.2-6 alkynyl", "C.sub.3-8 cycloalkyl", "heterocycloalkyl",
"aryl", "heteroaryl", and where R and R', together with the
nitrogen atom to which they are attached, can optionally form a
3-8-membered heterocycloalkyl ring.
[0175] "Amido" refers to the group --C(.dbd.O)NRR' where each R, R'
is independently hydrogen, "C.sub.1-6 alkyl", "C.sub.2-6 alkenyl",
"C.sub.2-6 alkynyl", "C.sub.3-8 cycloalkyl", "heterocycloalkyl",
"aryl", "heteroaryl", and where R and R', together with the
nitrogen atom to which they are attached, can optionally form a
3-8-membered heterocycloalkyl ring.
[0176] "Acylamino" refers to the group --NRC(O)R' wherein R and R'
are as defined hereabove for the amino group.
[0177] "Ureido" refers to the group --NR''C(O)NRR' wherein R and R'
are as defined hereabove for the amino group, and R'' is as defined
hereabove.
[0178] "Sulfanyl" refers to the group --SR where R is "C.sub.1-6
alkyl", "C.sub.2-6 alkenyl", "C.sub.2-6 alkynyl", "C.sub.3-8
cycloalkyl", "heterocycloalkyl", "aryl" or "heteroaryl".
[0179] "Sulfinyl" refers to the group --S(.dbd.O)R where R is
"C.sub.1-6 alkyl", "C.sub.2-6 alkenyl", "C.sub.2-6 alkynyl",
"C.sub.3-8 cycloalkyl", "heterocycloalkyl", "aryl" or
"heteroaryl".
[0180] "Sulfonyl" refers to the group --S(.dbd.O).sub.2R where R is
"C.sub.1-6 alkyl", "C.sub.2-6 alkenyl", "C.sub.2-6 alkynyl",
"C.sub.3-8 cycloalkyl", "heterocycloalkyl", "aryl" or
"heteroaryl".
[0181] "Alkylsulfonyl" refers to the group --S(.dbd.O).sub.2R
wherein R is an alkyl moiety, e.g. a "C.sub.1-6 alkyl".
[0182] "Halogen" refers to fluoro, chloro, bromo and iodo
atoms.
[0183] "Substituted or unsubstituted": Unless otherwise constrained
by the definition of the individual substituent, the above set out
groups, like "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl"
etc. groups can optionally be substituted with from 1 to 5
substituents selected from the group consisting of "C.sub.1-6
alkyl", "C.sub.2-6 alkenyl", "C.sub.2-6 alkynyl", "cycloalkyl",
"heterocycloalkyl", "amino", "amido", "acylamino", "ureido",
"aryl", "heteroaryl", "alkoxy", "halogen", cyano, hydroxy,
mercapto, nitro, "amido", "sulfanyl", "sulfinyl", "sulfonyl" and
the like.
[0184] The "pharmaceutically acceptable salts" according to the
invention include therapeutically active, non-toxic acid or base
salt forms which the compounds of formula (I) are able to form.
[0185] The acid addition salt form of a compound of formula (I)
that occurs in its free form as a base can be obtained by treating
the free base with an appropriate acid such as an inorganic acid,
for example, a hydrohalic such as hydrochloric or hydrobromic,
sulfuric, nitric, phosphoric and the like; or an organic acid, such
as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic,
lactic, pyruvic, malonic, succinic, maleic, fumaric, malic,
tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,
p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic
and the like.
[0186] The compounds of formula (I) containing acidic protons may
be converted into their therapeutically active, non-toxic base
addition salt forms, e.g. metal or amine salts, by treatment with
appropriate organic and inorganic bases. Appropriate base salt
forms include, for example, ammonium salts, alkali and earth
alkaline metal salts, e.g. lithium, sodium, potassium, magnesium,
calcium salts and the like, salts with organic bases, e.g.
N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids
such as, for example, arginine, lysine and the like.
[0187] Conversely said salt forms can be converted into the free
forms by treatment with an appropriate base or acid.
[0188] Compounds of the formula (I) and their salts can be in the
form of a solvate, which is included within the scope of the
present invention. Such solvates include for example hydrates,
alcoholates and the like.
[0189] Many of the compounds of formula (I) and some of their
intermediates have at least one stereogenic center in their
structure. This stereogenic center may be present in a R or a S
configuration, said R and S notation is used in correspondence with
the rules described in Pure Appl. Chem., 45 (1976) 11-30.
[0190] The invention also relates to all stereoisomeric forms such
as enantiomeric and diastereoisomeric forms of the compounds of
formula (I) or mixtures thereof (including all possible mixtures of
stereoisomers).
[0191] With respect to the present invention reference to a
compound or compounds is intended to encompass that compound in
each of its possible isomeric forms and mixtures thereof, unless
the particular isomeric form is referred to specifically.
[0192] Compounds according to the present invention may exist in
different polymorphic forms. Although not explicitly indicated in
the above formula, such forms are intended to be included within
the scope of the present invention.
[0193] Some of the compounds of formula (I) may also exist in
tautomeric forms. Such forms although not explicity indicated in
the above formula are intended to be included within the scope of
the present invention.
[0194] The invention also includes within its scope pro-drug forms
of the compounds of formula (I) and its various sub-scopes and
sub-groups.
[0195] The compounds of formula (I) according to the invention can
be prepared analogously to conventional methods as understood by
the person skilled in the art of synthetic organic chemistry.
[0196] 1. Synthesis of Compounds of Formula I-A.
[0197] According to one embodiment, some compounds having the
general formula I-A wherein R.sup.4a is H, R.sup.1 and R.sup.3
having the same definitions as above for compounds of formula I-A,
may be prepared by transformation of a compound of formula II into
the corresponding amide of formula A-1, reaction of this amide with
formaldehyde and deprotection according to the equation:
##STR00023##
[0198] wherein R.sup.1 and R.sup.3 have the same definitions as
above for compounds of formula I-A. [0199] Amides of formula A-1
may be obtained from amines of formula II and N-benzylglycine, or
any suitable protected glycine derivative, under conventional
peptide synthesis conditions, using for example
N,N'-dicyclohexylcarbodiimide as a coupling agent. [0200] Compounds
of formula A-2 may be prepared by reaction of an amide of formula
A-1 with formaldehyde, for example by heating an amide of formula
A-1 in aqueous formaldehyde at a temperature comprised between 20
and 80.degree. C., or according to any conventional method known to
the person skilled in the art. [0201] Imidazolidinones of formula
I-A wherein R.sup.4a is H may be prepared by deprotection of a
compound of formula A-2 according to any conventional method known
to the person skilled in the art.
[0202] According to another embodiment, some compounds of formula
I-A wherein R.sup.4a is an activated aromatic group may be prepared
by reaction of a compound of formula I-A wherein R.sup.4a is H with
a compound of formula R.sup.4a--F according to the equation:
##STR00024##
[0203] wherein R.sup.1 and R.sup.3 have the same definitions as
above for compounds of formula I-A.
[0204] This reaction may be carried out in DMSO or EtOH, between
0.degree. C. and 60.degree. C., in the presence of an inorganic
base, for example K.sub.2CO.sub.3.
[0205] According to another embodiment, some compounds having the
general formula I-A wherein R.sup.4a is an aniline may be prepared
by conventional reduction of the corresponding compound of formula
I-A wherein R.sup.4a is a nitrophenyl. This transformation may be
performed according to conditions described by Cristau, P. et al.
in Tetrahedron (2003), 59 (40), 7859-7870.
[0206] According to another embodiment, some compounds having the
general formula I-A wherein R.sup.4a is a phenyl moiety may be
prepared by reduction of the corresponding compound of formula I-A
wherein R.sup.4a is an aniline. This reaction may be carried out
using the conditions described by Van Loon, A. et al. in Recl.
Tray. Chim. Pays-Bas (1960), 79, 977.
[0207] 2. Synthesis of Compounds of Formula I-B1.
[0208] According to another embodiment, some compounds having the
general formula I-B1 may be prepared by transformation of a
compound of formula B1-1 into the corresponding thiazolidinone of
formula IV-B1 and subsequent reaction with a compound of formula
III according to the equation:
##STR00025##
[0209] wherein Hal is a halogen atom, preferably Br, and R.sup.1,
R.sup.3 and R.sup.4a are defined as hereabove for compounds of
formula I-B1. [0210] Intermediates of formula B1-1 may be prepared
following the procedure described by Gaupp, S. and Effenberger, F.
in Tetrahedron: Asymmetry (1999), 10 (9), 1777-1786. [0211]
Cyclization of aminothiols of formula B1-1 into thiazolidinones of
formula IV-B1 is performed in the presence of phosgene and an
inorganic base, in a mixture of solvents such as toluene/water.
[0212] Compounds of formula I-B1 may be obtained by alkylation of a
thiazolidinone of formula IV-B1 with a compound of formula III.
This reaction may be carried out with a strong base, preferably NaH
or KOH, in an inert solvent such as DMF, THF or acetone at a
temperature between 0.degree. C. and 60.degree. C.
[0213] According to another embodiment, some compounds of formula
I-B1 wherein R.sup.4a is --CH.sub.2CF.sub.3 may be prepared by
transformation of a compound of formula B1-2 into the corresponding
thiazolidinone of formula I-B1 according to the equation
##STR00026##
[0214] wherein R.sup.4a is --CH.sub.2CF.sub.3, R.sup.1 and R.sup.3
having the same definitions as described above for compounds of
formula I-B1. [0215] Compounds of formula B1-3 may be prepared as
follows:
[0215] ##STR00027## [0216] wherein LG is a suitable leaving group,
including halogen, --OC(O)alkyl,
--OSO.sub.2-C.sub.6H.sub.4--CH.sub.3,
--OSO.sub.2--C.sub.6H.sub.4--Br,
--OSO.sub.2--C.sub.6H.sub.4--NO.sub.2, --OSO.sub.2--CH.sub.3,
--OSO.sub.2--CF.sub.3, --OSO.sub.2--C.sub.4F.sub.9,
--OSO.sub.2--CH.sub.2--CF.sub.3,
--OSO.sub.2--(CH.sub.2).sub.n--N.sup.+Me.sub.3, --OSO.sub.2--F or
--OClO.sub.3. [0217] Compounds of formula B1-2 wherein R.sup.4a is
--CH.sub.2CF.sub.3 may be prepared by treating a compound of
formula B1-3 with carbon disulfide and an inorganic base such as
Cs.sub.2CO.sub.3, in an inert solvent such as DMF and at room
temperature. [0218] Compounds of formula I-B1 may be prepared from
thiazolidine thiones of formula B1-2 using potassium permanganate
and benzoic acid under the conditions described by Aitken, R. A. et
al. in Synthesis (1997), 7, 787-791.
[0219] 3. Synthesis of Compounds of Formula I-B2.
[0220] According to another embodiment, some compounds having the
general formula I-B2 wherein X is S may be prepared by
transformation of a compound of formula V into the corresponding
thiocarbonate of formula VIII-B2 followed by condensation with an
amine of formula II according to the equation:
##STR00028##
[0221] wherein X is S, R.sup.1, R.sup.4a and R.sup.3 having the
same definitions as described above for compounds of formula I-B2.
[0222] Compounds of formula VIII-B2 may be prepared by reaction of
an aldehyde of formula V and methoxycarbonylsulfenylchloride in
CHCl.sub.3 at room temperature as described by Sanemitsu, Y. et al.
in J. Org. Chem. (1992), 57 (3), 1053-1056. [0223] Compounds of
formula I-B2 may be prepared by condensation of a compound of
formula VIII-B2 with a compound of formula II in toluene under acid
catalysis, for example in the presence of p-toluenesulfonic
acid.
[0224] According to another embodiment, some compounds having the
general formula I-B2 wherein X is S and R.sup.4a is
--CH.sub.2R.sup.4c may be prepared by transformation of a compound
of formula B2-3 into the corresponding thiocarbamate of formula
B2-2 followed by reduction/dehydration according to the
equation:
##STR00029##
[0225] wherein R.sup.4a is --CH.sub.2R.sup.4c, R.sup.4c is hydrogen
or C.sub.1-5 alkyl optionally substituted by halogen or C.sub.1-4
alkoxy, X is S, Hal is halogen, preferably Br, and R.sup.3 has the
same definitions as described above for compounds of formula I-B2.
[0226] Compounds of formula B2-4 may be prepared from a
thiazolidine-dione of formula B2-6 and an aldehyde of formula B2-5
(both available from commercial sources) by heating in acetic acid
in the presence of sodium acetate according to the procedure
described in Dundar, B. et al. in Pharmazie (2002), 57 (7),
438-441. [0227] Compounds of formula B2-3 may be obtained by
alkylation of a compound of formula B2-4 with a compound of formula
Ill. This reaction may be carried out with an inorganic base such
as K.sub.2CO.sub.3, in an inert solvent such as DMF, at a
temperature comprised between 0.degree. C. and 35.degree. C. [0228]
Compounds of formula B2-2 may be prepared by hydrogenation of a
compound of formula B2-3. This transformation may be performed
according to any method known to the person skilled in the art.
[0229] Reduction of the carbonyl group of compounds B2-2 to
compounds of formula B2-1 may be performed according to any method
known to the person skilled in the art. [0230] Compounds of formula
I-B2 may be obtained by dehydration of compounds of formula B2-1,
for example by refluxing in acetic acid.
[0231] 4. Synthesis of Compounds of Formula I-B3.
[0232] According to another embodiment, some compounds having the
general formula I-B3 may be prepared by transformation of a
compound of formula II into the corresponding thiocarbamate of
formula B3-1 followed by cyclization according to the equation:
##STR00030##
[0233] wherein R.sup.1, R.sup.4a and R.sup.3 have the same
definitions as described above for compounds of formula I-B3.
[0234] Compounds of formula B3-2 may be prepared by alkylating
compounds of formula II with allylbromide. This alkylation may be
performed as described for the preparation of compounds of formula
B2-2. [0235] Compounds of formula B3-1 may be obtained by treatment
of compounds of formula B3-2 with methylchloroformate in
CH.sub.2Cl.sub.2, between 0.degree. C. and room temperature, in the
presence of an inorganic base such as K.sub.2CO.sub.3. [0236]
Compounds of formula I-B3 may be prepared by treating compounds of
formula B3-1 with iodine and potassium iodide in CH.sub.2Cl.sub.2
and at room temperature.
[0237] 5. Synthesis of Compounds of Formula I-C.
[0238] According to another embodiment, some compounds having the
general formula I-C wherein R.sup.4a is H may be prepared by
transformation of a compound of formula II into the corresponding
pyrrol of formula C-1 followed by oxydation according to the
equation:
##STR00031##
[0239] wherein R.sup.1 and R.sup.3 have the same definitions as
described above for compounds of formula I-C. [0240] Pyrroles of
formula C-1 may be obtained by refluxing an amine of formula II and
2,5-dimethoxytetrahydrofuran in acetic acid. [0241] Compounds of
formula I-C may be prepared by oxidation of pyrroles of formula C-1
with m-CPBA. This oxidation step may be performed in refluxing
chloroform in the presence of an inorganic base such as
K.sub.2CO.sub.3.
[0242] According to another embodiment, some compounds having the
general formula I-C wherein R.sup.4a is --CH.sub.2R.sup.4d may be
prepared by transformation of a compound of formula C-2 according
to the equation:
##STR00032##
[0243] wherein R.sup.1 and R.sup.3 have the same definitions as
described above for compounds of formula I-C, R.sup.4a is
--CH.sub.2R.sup.4d and R.sup.4d is H or C.sub.1-5 alkyl. [0244]
Compounds of formula C-2 may be prepared as described in Kenda B.
et al in J. Med. Chem. (2004), 47, 530, or in PCT patent
applications WO 01/62726 and WO 2006/128692. [0245] Compounds of
formula I-C may be obtained by treatment of a compound of formula
C-2 with a base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene, in
an inert solvent such as DMF, at a temperature comprised between
20.degree. C. and 90.degree. C.
[0246] According to another embodiment, some compounds having the
general formula I-C may be prepared by transformation of compound
of formula C-3 according to the equation:
##STR00033##
[0247] wherein R.sup.1, R.sup.3 and R.sup.4d have the same
definitions as described above for compounds of formula I-C. [0248]
Compounds of formula C-3 may be prepared as described in Kenda B.
et al in J. Med. Chem. (2004), 47, 530 or in PCT patent
applications WO 01/62726 and WO 2006/128692. [0249] Compounds of
formula I-C may be prepared by reductive amination of a
hydroxylactone of formula C-3 with an amine of formula II as
described in PCT patent applications WO 01/62726 and WO
2006/128692.
[0250] 6. Synthesis of Compounds of Formula I-D1.
[0251] According to another embodiment, some compounds having the
general formula I-D1 may be prepared by alkylation of a compound of
formula IV-D1 according to the equation:
##STR00034##
[0252] wherein R.sup.1, R.sup.4a and R.sup.3 have the same
definitions as described above for compounds of formula I-D1 and
Hal is halogen, preferably Br. [0253] Compounds of formula IV-D1
are available from commercial sources or may be prepared as
described by Johnson, T. A. et al. in J. Am. Chem. Soc. (2002), 124
(39),11689-11698; by Milewska, M. J. et al. in Synthesis (1996),
12, 1485-1488; and by Burger, A. and Hofstetter, A. in J. Org.
Chem. (1959), 24, 1290; or according to any other method known to
the person skilled in the art. [0254] Compounds of formula I-D1 may
be prepared by alkylation of a compound of formula III with a
compound of formula IV-D1. This reaction may be performed as
described for the synthesis of compounds of formula I-B1.
[0255] According to another embodiment, some compounds having the
general formula I-D1 wherein R.sup.4a is an imidazolyl, an
imidazopyridinyl or an imidazopyridazinyl may be prepared by
N-alkylation of compound of formula IV-D1 according to the
equation:
##STR00035##
[0256] wherein R.sup.1 and R.sup.3 have the same definitions as
described above for compounds of formula I-D1. [0257] Compounds of
formula D1-2 may be prepared by hydroxyalkylation of a compound of
formula IV-D1 with a carbonyl derivative of formula VI as described
in PCT patent applications WO 2005/054188 and WO 2006/128692. This
reaction may be carried out by heating a lactam of formula IV-D1
with an aldehyde of formula VI (or its synthetic equivalent such as
paraformaldehyde in the case of formaldehyde) eventually in the
presence of a base such as KOH and in a solvent such as water or a
solvent mixture such as MeOH/water. [0258] The synthesis of
intermediates of formula D1-1 may be carried out using
thionylchloride in toluene at a temperature between 0.degree. C. to
room temperature. [0259] Some compounds having the general formula
I-D1 may be prepared by chlorination of a compound of formula D1-2
and condensation of the corresponding derivative of formula D1-1
with a heterocycle of formula R.sup.3H as described in PCT patent
applications WO 2005/054188 and WO 2006/128692.
[0260] According to another embodiment, some compounds having the
general formula I-D1 may be prepared by reductive amination of
compound of formula IX-D1a according to the equation:
##STR00036##
[0261] wherein R.sup.1, R.sup.4a and R.sup.3 have the same
definitions as described above for compounds of formula I-D1 and
R.sup.i is a C.sub.1-4 alkyl. [0262] Imines of formula D1-3 may be
prepared by heating commercially available aldehydes of formula V
and piperidine using conditions known to the person skilled in the
art. [0263] Compounds of formula VIII-D1a may be prepared from of
formula D1-3 and ethylacrylate in an inert solvent such as
acetonitrile at a temperature ranging from 0.degree. C. to
80.degree. C., followed by hydrolysis of the intermediate imine by
heating in a mixture of acetic acid and water at a temperature of
90.degree. C. [0264] Compounds of formula X-D1a may be prepared by
reductive amination of compounds of formula VIII-D1a with
tert-butyl carbamate according to any method known to the person
skilled in the art. [0265] Compounds of formula IX-D1a can be
prepared by treating compounds of formula X-D1a with a strong acid
such as HCl, in a solvent such as dioxane, or according to any
other method known to the person skilled in the art. [0266]
Compounds of formula I-D1 may be prepared by reductive amination of
the carbonyl derivative of formula VII with an amino acid
derivative of formula IX-D1a using the procedures described in PCT
patent applications WO 01/62726 and WO 2006/128692.
[0267] According to another embodiment, some compounds having the
general formula I-D1 wherein may be prepared by reductive amination
of compound of formula VIII-D1 according to the equation:
##STR00037##
[0268] wherein R.sup.1, R.sup.4a and R.sup.3 have the same
definitions as described above for compounds of formula I-D1 and
R.sup.i is a C.sub.1-4 alkyl. [0269] Compounds VIII-D1 are
commercially available or may be prepared as described for the
synthesis of VIII-D1a. [0270] Some compounds of formula I-D1 may be
prepared by reductive amination of a carbonyl derivative of formula
VIII-D1 as described in PCT patent applications WO 01/62726 and WO
2006/128692.
[0271] According to another embodiment, some compounds having the
general formula I-D1 may be prepared by alkylation of compound of
formula XI-D1 according to the equation:
##STR00038##
[0272] wherein R.sup.1, R.sup.4a and R.sup.3 have the same
definitions as described above for compounds of formula I-D1 and
R.sup.i is a C.sub.1-4 alkyl. [0273] Compounds of formula XI-D1 are
commercially available or may be prepared according to the method
described by Jones, J. B. and Lok, K. P. in Can. J. Chem. (1979),
57, 1025-1032 or by Burger and Hofstetter in J. Org. Chem. (1959),
24, 1290. [0274] Compounds of formula I-D1 may be prepared by
substitution of a compound of formula XI-D1 with an amine of
formula II. This reaction is performed by refluxing in CH.sub.3CN
as solvent in the presence of an inorganic base such as
Cs.sub.2CO.sub.3.
[0275] 7. Synthesis of Compounds of Formula I-D2.
[0276] According to another embodiment, some compounds having the
general formula I-D2 may be prepared from the protected lactam of
formula XIV-D2 according to the equation:
##STR00039##
[0277] wherein R.sup.1, R.sup.4a and R.sup.3 have the same
definitions as described above for compounds of formula I-D2 and
R.sup.i is C.sub.1-4 alkyl. [0278] Some compounds XIV-D2 may be
synthesized as a mixture of isomers according to the equation:
[0278] ##STR00040## [0279] Compounds of formula D2-1 may be
synthesized as described by H. O. House, W. F. Fisher in J. Org.
Chem. (1969), 34, 3615-3618. [0280] Compounds of formula IV-D2a and
IV-D2b may be prepared by a Beckmann rearrangement. This
transformation may be performed by treating a compound of formula
D2-1 with sodiumazide and methanesulfonic acid in a solvent such as
CHCl.sub.3 and at a temperature ranging from 0.degree. C. to room
temperature. [0281] Compounds of formula XIV-D2a and XIV-D2b may be
prepared from compounds of formula IV-D2a and IV-D2b using methods
known to the person skilled in the art. [0282] Compounds of formula
X-D2 may be prepared by ring opening of a tBoc-protected lactam of
formula XIV-D2. This transformation may be performed by treating
compounds of formula XIV-D2 with sodium methoxide in methanol at a
temperature between 0.degree. C. and 5.degree. C. [0283]
Deprotection of compounds of formula X-D2 into IX-D2 is performed
under conditions known to the person skilled in the art. [0284]
Compounds having the general formula XIII-D2 may be prepared by
reductive amination of the carbonyl derivative of formula VII with
a compound of formula IX-D2 according to the method described in
PCT patent applications WO 01/62726 and WO 2006/128692. [0285]
Compounds of formula XII-D2 may be prepared by hydrolysis of
compounds of formula XIII-D2. This transformation may be performed
according to any method known to the person skilled in the art.
[0286] Compounds of formula I-D2 may be obtained from compounds of
formula XII-D2 under conventional peptide synthesis conditions, by
using coupling agents, for example
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate, or according to any other method known to the
person skilled in the art.
[0287] 8. Synthesis of Compounds of Formula I-F1.
[0288] According to another embodiment, some compounds having the
general formula I-F1 may be prepared from the protected anilines of
formula F1-2 according to the equation:
##STR00041##
[0289] wherein R.sup.1, R.sup.4b and R.sup.3 have the same
definitions as described above for compounds of formula I-F1 and
Hal is a halogen atom, preferably Br. [0290] Compounds of formula
F1-1 may be prepared by acylation of anilines of formula F1-2 with
3-chloropropanoyl chloride in a solvent such as acetone, at a
temperature ranging from 0.degree. C. to 56.degree. C. [0291]
Compounds of formula IV-F1 may be prepared by heating compounds of
formula F1-1 with a Lewis acid, such as AlCl.sub.3, at high
temperature (140.degree. C. as an example). [0292] Compounds of
formula I-F1 may be obtained by alkylation of compounds of formula
IV-F1 by compounds of formula III. This reaction may be carried
using the conditions described for the synthesis of I-B1.
[0293] 9. Synthesis of Compounds of Formula I-F2.
[0294] According to another embodiment, some compounds having the
general formula I-F2 may be prepared from the protected anilines
F2-3 according to the equation:
##STR00042##
[0295] wherein R.sup.1, R.sup.4b and R.sup.3 have the same
definitions as described above for compounds of formula I-F2 and
R.sup.i is methyl. [0296] Compounds of formula F2-3 are available
from commercial sources. [0297] Compounds of formula F2-2 may be
prepared from compounds of formula F2-3 by treatment with t-butyl
acetate in the presence of P(t-Bu) and Pd(dba)2 in a solvent such
as toluene and in the presence of a base such as LiHMDS. [0298] The
transformation of compounds of formula F2-2 into compounds of
formula F2-1 may be performed by transesterification in MeOH in the
presence of HCl between 50 and 55.degree. C. [0299] Compounds of
formula XI-F2 may be obtained from compounds of formula F2-1 in the
presence of N-bromosuccinimide and benzoylperoxide, in an inert
solvent such as benzene, and at room temperature. [0300] Compounds
of formula I-F2 may be prepared by heating compounds of formula
XI-F2 and compounds II in acetonitrile at a temperature comprised
between 75.degree. C. and 80.degree. C.
[0301] According to another embodiment, some compounds having the
formula I-F2 wherein R.sup.3 is CONH.sub.2 may be prepared by
aminolysis of a compound of formula F2-4
##STR00043##
[0302] wherein R.sup.1 and R.sup.4b have the same definitions as
described above for compounds of formula I-F2. This transformation
may be performed in MeOH saturated with gaseous ammonia at room
temperature.
[0303] 10. Synthesis of Compounds of Formula I-F3.
[0304] According to another embodiment, some compounds having the
general formula I-F3 may be prepared from the protected anilines of
formula IV-F3 according to the equation:
##STR00044##
[0305] wherein R.sup.1, R.sup.3 and R.sup.4b have the same
definitions as described above for compounds of formula I-F3.
[0306] Compounds of formula IV-F3 may be prepared as described by
Molloy, Bryan B. in Canadian patent applications CA 1122528 and CA
1119592 and are obtained as a mixture of isomers IV-F3 and IV-F4
(see below). [0307] Compounds of formula XIV-F3 may be prepared
from benzazepines of formula IV-F3 using standard procedures known
to the person skilled in the art. [0308] Compounds of formula XV-F3
may be prepared by ring opening of compounds of formula XIV-F3.
This transformation may be performed by treating compounds of io
formula XIV-F3 with LiOH in a solvent such as THF. [0309] Compounds
of formula XVI-F3 may be prepared from compounds of formula XV-F3
according to any method known to the person skilled in the art.
[0310] Compounds having the general formula XII-F3 may be prepared
by reductive amination of a carbonyl derivative of formula VII with
a compound of formula XVI-F3, according to any method known to the
person skilled in the art. [0311] Compounds of formula I-F3 may be
obtained from compounds of formula XII-F3 under conventional
peptide synthesis conditions, by using coupling agents, for example
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate.
[0312] According to another embodiment, some compounds of formula
I-F3 may be prepared by alkylation of a compound of formula IV-F3
with a compound of formula III according to the equation:
##STR00045##
[0313] wherein R.sup.1, R.sup.3 and R.sup.4b have the same
definitions as described above for compounds of formula I-F3 and
Hal is a halogen, preferably Br. This reaction may be carried out
in an inert solvent such as THF, in the presence of a strong base
such as n-BuLi, at a temperature ranging from -70.degree. C. to
60.degree. C.
[0314] According to another embodiment, some compounds having the
general formula I-F3 or I-F2 wherein R.sup.3 is 1H-imidazol-4-yl
may be prepared from the corresponding trityl protected imidazoles
of formula I-F3 or I-F4 according to the equation:
##STR00046##
[0315] wherein R.sup.1 and R.sup.4b have the same definitions as
described above for compounds of formula I-F3 or I-F2. This
transformation may performed by heating the starting product with a
strong acid such as HCl, eventually in the presence of a solvent
such as dioxane, at a temperature ranging from room temperature to
100.degree. C.
[0316] 11. Synthesis of Compounds of Formula I-F4.
[0317] Compounds of formula I-F4 may be synthesized following the
same procedure as for the synthesis of compounds of formula I-F3,
using intermediate of formula IV-F4 instead of its isomer IV-F3,
according to the equation:
##STR00047##
[0318] wherein R.sup.1, R.sup.3 and R.sup.4b have the same
definitions as described above for compounds of formula I-F4.
[0319] 12. Synthesis of Compounds of Formula I-G1.
[0320] According to another embodiment, some compounds having the
general formula I-G1 may be prepared from the nitro-thiophene
derivatives of formula G1-4 according to the equation:
##STR00048##
[0321] wherein R.sup.1, R.sup.3 and R.sup.4b have the same
definitions as described above for compounds of formula I-G1 and
Hal is a halogen atom, preferably Br. [0322] Compounds of formula
G1-3 may be prepared from compounds of formula G1-4 (available from
commercial sources or synthesized using know procedure from
literature) by treatment with di(tertbutyl) malonate in the
presence of a strong base such as NaH, in an inert solvent, for
example DMSO, at a temperature ranging from room temperature to
100.degree. C. [0323] Compounds of formula G1-2 may be prepared by
decarboxylation of compounds of formula G1-3. This reaction is
performed by refluxing compounds of formula G1-3 in TFA. [0324]
Compounds of formula G1-1 may be obtained from compounds of formula
G1-2 using standard procedures known to the person skilled in the
art. [0325] Compounds of formula I-G1 may be prepared by reaction
of a compound of formula G1-1 with a compound of formula III by
heating with micro waves (200 W) in an inert solvent such as THF at
a temperature of 100.degree. C.
[0326] According to another embodiment, some compounds having the
general formula I-G1 may be prepared from the nitro-thiophene
derivatives of formula G1-3 according to the equation:
##STR00049##
[0327] wherein R.sup.1, R.sup.3 and R.sup.4b have the same
definitions as described above for compounds of formula I-G1.
[0328] Compounds of formula G1-7 may be prepared from compounds of
formula G1-3 according to reduction conditions known to the person
skilled in the art. [0329] The transformation of compounds of
formula G1-7 into compounds of formula G1-6 may be performed by
reductive amination with a carbonyl compounds of formula VII
according to the methods described in PCT patent applications WO
01/62726 and WO 2006/128692. [0330] Compounds of formula G1-5 may
be prepared by decarboxylation of compounds of formula G1-6. This
reaction may be performed by heating compounds of formula G1-6 in
6N HCl at a temperature ranging from 70.degree. C. to 75.degree. C.
[0331] Compounds of formula I-G1 may be obtained starting from
compounds of formula G1-5 under conventional peptide synthesis
conditions, for example by using coupling agents such as
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate.
[0332] 13. Synthesis of Compounds of Formula I-G2.
[0333] According to another embodiment, some compounds having the
general formula I-G2 may be prepared from the thiophene G1-7
according to the equation:
##STR00050##
[0334] wherein R.sup.1, R.sup.3 and R.sup.4b have the same
definitions as described above for compounds of formula l-G2.
[0335] The transformation of compounds of formula G1-7 into
compounds of formula G2-1 may be performed in a mixture of solvents
such as dichloroethane/trifluoroacetic acid, in the presence of
triethylsilane, at a temperature comprised between room temperature
and 40.degree. C. [0336] Compounds of formula I-G2 may be prepared
by treating compounds of formula G2-1 with a reducing agent such as
Na(CN)BH.sub.3 in acetic acid at room temperature, or according to
any other method known to the person skilled in the art.
[0337] 14. Synthesis of Compounds of Formula I-G3.
[0338] According to another embodiment, some compounds having the
general formula I-G3 may be prepared from compounds of formula G3-5
according to the equation:
##STR00051##
[0339] wherein R.sup.1, R.sup.3 and R.sup.4b have the same
definitions as described above for compounds of formula I-G3.
[0340] Compounds of formula G3-4 may be prepared from compounds of
formula G3-5 by a Curtius rearrangement. This transformation may be
performed using the conditions described by Shiori, T. et al. in J.
Am. Chem. Soc. (1972), 94, 6203. [0341] Compounds of formula G3-3
may be obtained from compounds of formula G3-4 using standard
procedures known to the person skilled in the art. [0342] Compounds
of formula G3-2 may be prepared using the same procedure as for the
synthesis of G1-5. [0343] Compounds of formula G3-1 may be prepared
by saponification of compounds of formula G3-2 using standard
procedures known to the person skilled in the art. [0344] Compounds
of formula I-G3 may be prepared from compounds of formula G3-1
under conventional peptide synthesis conditions, for example by
using a coupling agent such as
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU).
[0345] 15. Synthesis of Compounds of Formula I-E.
[0346] According to another embodiment, some compounds having the
general formula I-E may be prepared from compounds of formula IV-E
according to the equation:
##STR00052##
[0347] wherein R.sup.1, R.sup.3, R.sup.4b and X have the same
definitions as described above for compounds of formula I-E. This
reaction may be performed using the conditions described for the
synthesis of compounds of formula I-B1.
[0348] According to another embodiment, some compounds having the
general formula I-E wherein R.sup.1 is hydrogen and R.sup.3 is an
imidazolyl, an imidazopyridinyl or an imidazopyridazinyl may be
prepared from derivatives of formula IV-E according to the
equation:
##STR00053##
[0349] wherein R.sup.1 is hydrogen and R.sup.3 is an imidazolyl, X
and R.sup.4b having the same definitions as described above for
compounds of formula I-E. [0350] Compounds of formula E-2 may be
prepared by hydroxyalkylation of IV-E using the same conditions as
described for the synthesis of compounds of formula D1-2. [0351]
Compounds of formula E-1 may be prepared as described for
intermediates of formula D1-1. [0352] Some compounds of formula I-E
wherein R.sup.3 is imidazolyl may be prepared in one step by
heating a compound E-2 with carbonyldiimidazole in a solvent such
as acetonitrile.
[0353] According to another embodiment, some compounds having the
general formula I-E wherein R.sup.4b is Cl may be prepared by
reaction of corresponding compound of formula I-E wherein R.sup.4b
is hydrogen with N-chlorosuccinimide in concentrated
H.sub.2SO.sub.4, at a temperature comprised between 0.degree. C.
and room temperature.
[0354] 16. Synthesis of Compounds of Formula I-H1.
[0355] According to another embodiment, some compounds having the
general formula I-H1 may be prepared from compounds of formula
IV-H1 according to the equation:
##STR00054##
[0356] wherein Hal is halogen, preferably Br, and R.sup.1, R.sup.3,
R.sup.4a and R.sup.8 have the same definitions as described above
for compounds of formula I-H1. This reaction may be performed using
the conditions described for the synthesis of compounds of formula
I-B1.
[0357] According to another embodiment, some compounds having the
general formula I-H1 wherein R.sup.3 is --CONH.sub.2 may be
prepared according to the equation:
##STR00055##
[0358] wherein Hal is halogen, preferably Br, R.sup.X is C.sub.1-4
alkyl and R.sup.1, R.sup.3, R.sup.4a and R.sup.8 have the same
definitions as described above for compounds of formula I-H1.
[0359] Compounds of formula H1-1 may be prepared using the
conditions described for the synthesis of compounds of formula
I-B1. [0360] Compounds of formula I-H1 may be prepared by direct
ammonolysis of intermediates of formula H1-1 according to any
method known to the person skilled in the art.
[0361] Compounds of formula IV-H1 wherein R.sup.8 is CN may be
prepared according to the equation
##STR00056## [0362] Compounds of formula H1-2 may be prepared by
reaction of a compound of formula H1-3 with a trimethyloxonium
borofluoride in dry dichloromethane at room temperature, or
according to any method known to the person skilled in the art.
[0363] Compounds of formula IV-H1 may be prepared by reaction of a
compound of formula H1-2 with cyanamide at room temperature, or
according to any method known to the person skilled in the art.
[0364] Compounds of formula IV-H1 wherein R.sup.8 is C.sub.1-6
alkylsulfonyl may be prepared by reaction of a compound of formula
H1-2 with an alkylsulfonamide of formula H1-4 according to the
equation:
##STR00057##
[0365] wherein R.sup.t is a C.sub.1-6 alkyl. This reaction may be
performed in a solvent such as methanol, at reflux temperature and
under anhydrous conditions, or according to any method known to the
person skilled in the art.
[0366] 17. Synthesis of Compounds of Formula I-H2.
[0367] According to another embodiment, some compounds having the
general formula I-H2 may be prepared from compounds of formula
IV-H2 according to the equation:
##STR00058##
[0368] wherein Hal is halogen, preferably Br, and R.sup.1, R.sup.3,
R.sup.4a and R.sup.8 have the same definitions as described above
for compounds of formula I-H2. This reaction may be performed using
the conditions described for the synthesis of compounds of formula
I-B1.
[0369] According to another embodiment, some compounds having the
general formula I-H2 wherein R.sup.3 is --CONH.sub.2 may be
prepared according to the equation:
##STR00059##
[0370] wherein Hal is halogen, preferably Br, R.sup.X is C.sub.1-4
alkyl and R.sup.1, R.sup.3, R.sup.4a and R.sup.8 have the same
definitions as described above for compounds of formula I-H1.
[0371] Compounds of formula H2-1 may be prepared using the
conditions described for the synthesis of compounds of formula
I-B1. [0372] Compounds of formula I-H2 may be prepared by direct
ammonolysis of intermediates of formula H2-1 according to any
method known to the person skilled in the art.
[0373] Compounds of formula IV-H2 wherein R.sup.8 is CN may be
prepared according to the equation
##STR00060##
[0374] using the method described for the synthesis of compounds of
formula IV-H1. Compounds of formula IV-H1 wherein R.sup.8 is
C.sub.1-6 alkylsulfonyl may be prepared by reaction of a compound
of formula H1-2 with an alkylsulfonamide of formula H1-4 according
to the equation:
##STR00061##
[0375] wherein R.sup.t is a C.sub.1-6 alkyl, using the method
described for the synthesis of compounds of formula IV-H1.
[0376] 18. Synthesis of Compounds of Formula I-H3.
[0377] According to another embodiment, some compounds having the
general formula I-H3 may be prepared from compounds of formula
IV-H3 according to the equation:
##STR00062##
[0378] wherein Hal is halogen, preferably Br, and R.sup.1, R.sup.3,
R.sup.4a and R.sup.8 have the same definitions as described above
for compounds of formula I-H3. This reaction may be performed using
the conditions described for the synthesis of compounds of formula
I-B1.
[0379] According to another embodiment, some compounds having the
general formula I-H3 wherein R.sup.3 is --CONH.sub.2 may be
prepared according to the equation:
##STR00063##
[0380] wherein Hal is halogen, preferably Br, R.sup.X is C.sub.1-4
alkyl and R.sup.1, R.sup.3, R.sup.4a and R.sup.8 have the same
definitions as described above for compounds of formula I-H3.
[0381] Compounds of formula H3-1 may be prepared using the
conditions described for the synthesis of compounds of formula
I-B1. [0382] Compounds of formula I-H3 may be prepared by direct
ammonolysis of intermediates of formula H3-1 according to any
method known to the person skilled in the art.
[0383] Compounds of formula IV-H3 wherein R.sup.8 is CN may be
prepared according to the equation
##STR00064##
[0384] using the method described for the synthesis of compounds of
formula IV-H3. Compounds of formula IV-H3 wherein R.sup.8 is
C.sub.1-6 alkylsulfonyl may be prepared by reaction of a compound
of formula H3-2 with an alkylsulfonamide of formula H1-4 according
to the equation:
##STR00065##
[0385] wherein R.sup.t is a C.sub.1-6 alkyl, using the method
described for the synthesis of compounds of formula IV-H1.
[0386] According to another embodiment, the present invention
consist in novel compounds selected from the group consisting of:
(2S)-2-{[(benzylamino)acetyl]amino}butanamide;
(2S)-2-(3-benzyl-5-oxoimidazolidin-1-yl)butanamide;
(2S)-2-(5-oxoimidazolidin-1-yl)butanamide;
(2S)-2-[3-(4-aminophenyl)-5-oxoimidazolidin-1-yl]butanamide;
(2S)-2-(allylamino)butanamide; methyl
allyl[(1S)-1-(aminocarbonyl)propyl]carbamate;
(2S)-2-(1H-pyrrol-1-yl)butanamide; methyl
4-{[(1S)-1-(aminocarbonyl)propyl]amino}-3-phenylbutanoate;
S-(1-formylbutyl)O-methyl thiocarbonate;
2-(2,4-dioxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;
2-(4-hydroxy-2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;
1-cyanopentyl 4-methylbenzenesulfonate;
S-[cyano(phenyl)methyl]ethanethioate;
S-(1-cyanopentyl)ethanethioate; 5-butyl-1,3-thiazolidin-2-one;
5-propyl-1,3-thiazolidin-2-one;
(2S)-2-[2-thioxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide-
; 1-(hydroxymethyl)-5-phenylpiperidin-2-one;
6-fluoro-3-(hydroxymethyl)-1,3-benzoxazol-2(3H)-one;
1-(hydroxymethyl)-5-propylpiperidin-2-one;
1-(hydroxymethyl)-4-phenylpiperidin-2-one;
1-(hydroxymethyl)-4-propylpiperidin-2-one;
1-(chloromethyl)-5-phenylpiperidin-2-one;
3-(chloromethyl)-6-fluoro-1,3-benzoxazol-2(3H)-one;
1-(chloromethyl)-5-propylpiperidin-2-one;
1-(chloromethyl)-4-phenylpiperidin-2-one; ethyl 4-formylheptanoate;
ethyl 4-{[(tert-butoxycarbonyl)amino]methyl}heptanoate; ethyl
4-(aminomethyl)heptanoate hydrochloride; ethyl
3-(2-bromoethyl)hexanoate; tert-butyl
2-oxo-5-propylazepane-1-carboxylate; tert-butyl
2-oxo-5-phenylazepane-1-carboxylate; 4-propylazepan-2-one;
6-propylazepan-2-one; tert-butyl
2-oxo-4-propylazepane-1-carboxylate; tert-butyl
2-oxo-6-propylazepane-1-carboxylate; methyl
4-{2-[(tert-butoxycarbonyl)amino]ethyl}heptanoate; methyl
6-[(tert-butoxycarbonyl)amino]-4-phenylhexanoate; methyl
5-{[(tert-butoxycarbonyl)amino]methyl}octanoate; methyl
6-[(tert-butoxycarbonyl)amino]-3-propylhexanoate; methyl
4-(2-aminoethyl)heptanoate hydrochloride; methyl
6-amino-4-phenylhexanoate; methyl 5-(aminomethyl)octanoate
hydrochloride; methyl 6-amino-3-propylhexanoate hydrochloride;
methyl 4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoate;
isopropyl
4-[2-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)ethyl]-
heptanoate; isopropyl
4-phenyl-6-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)-
hexanoate; methyl
5-{[(1H-imidazol-4-ylmethyl)amino]methyl}octanoate; methyl
6-[(1H-imidazol-4-ylmethyl)amino]-3-propylhexanoate;
4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoic acid
dihydrochloride;
4-[2-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)ethyl]-
heptanoic acid dihydrochloride;
4-phenyl-6-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)-
hexanoic acid dihydrochloride;
5-{[(1H-imidazol-4-ylmethyl)amino]methyl}octanoic acid
dihydrochloride; 6-[(1H-imidazol-4-ylmethyl)amino]-3-propylhexanoic
acid dihydrochloride; di-tert-butyl(3-nitro-2-thienyl)malonate;
di-tert-butyl(3-amino-2-thienyl)malonate;
di-tert-butyl{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}malonate;
{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}acetic acid
dihydrochloride;
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methylene}amino)-2-th-
ienyl]acetic acid;
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)-2-thien-
yl]acetic acid;
ethyl{4-[(tert-butoxycarbonyl)amino]-3-thienyl}acetate;
ethyl(4-amino-3-thienyl)acetate hydrochloride;
ethyl{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate; sodium
{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate;
1-{(3-ethoxy-3-oxopropanoyl)[(1-trityl-1H-imidazol-4-yl)methyl]amino}pyri-
dinium chloride; ethyl
2-oxo-1-[(1-trityl-1H-imidazol-4-yl)methyl]-1,2-dihydropyrazolo[1,5-a]pyr-
idine-3-carboxylate-methanol (1:2);
tert-butyl(5-chloro-2-methylphenyl)acetate;
methyl(5-chloro-2-methylphenyl)acetate; methyl
[2-(bromomethyl)-5-chlorophenyl]acetate; methyl
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoate;
tert-butyl (2-chloro-6-methylphenyl)acetate; methyl
(2-chloro-6-methylphenyl)acetate; methyl
[2-(bromomethyl)-6-chlorophenyl]acetate;
1-[(1-trityl-1H-imidazol-4-yl)methyl]-3,4-dihydroquinolin-2(1H)-one;
tert-butyl
7-chloro-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate;
tert-butyl
7-chloro-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate;
3-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorophenyl)propanoic
acid;
(2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-chlorophenyl)acetic
acid; 3-[2-(aminomethyl)-5-chlorophenyl]propanoic acid
hydrochloride; [2-(2-aminoethyl)-4-chlorophenyl]acetic acid
hydrochloride;
3-[5-chloro-2-({[(1-trityl-1H-imidazol-4-yl)methyl]amino}methyl)phenyl]pr-
opanoic acid;
[4-chloro-2-(2-{[(1-trityl-1H-imidazol-4-yl)methyl]amino}ethyl)phenyl]ace-
tic acid;
7-chloro-2-[(1-trityl-1H-imidazol-4-yl)methyl]-1,2,4,5-tetrahydr-
o-3H-2-benzazepin-3-one;
7-chloro-3-[(1-trityl-1H-imidazol-4-yl)methyl]-1,3,4,5-tetrahydro-2H-3-be-
nzazepin-2-one;
3-(chloromethyl)-2-(trifluoromethyl)-imidazo[1,2-a]pyridine;
5-methoxy-3-propyl-3,4-dihydro-2H-pyrrole;
[(2E)-4-propylpyrrolidin-2-ylidene]cyanamide; ethyl
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanoate; and
N-[(2E)-4-propylpyrrolidin-2-ylidene]methanesulfonamide; for their
use as synthetic intermediates.
[0387] In a further aspect, the present invention concerns also the
use of a compound of formula (I) or a pharmaceutically acceptable
salt thereof for the manufacture of a medicament for the treatment
of neurological and other disorders such as mentioned above.
[0388] In particular, the present invention concerns the use of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof for the manufacture of a medicament for the treatment of
epilepsy, Parkinson's disease, dyskinesia, migraine, tremor,
essential tremor, bipolar disorders, chronic pain, neuropathic
pain, or bronchial, asthmatic or allergic conditions. The compounds
of the present invention may also be useful in the treatment of
lower urinary tract disorders.
[0389] In a specific embodiment, the present invention concerns the
use of a compound selected from the group consisting of:
(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;
(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;
(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide;
2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;
2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;
2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;
2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;
(+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;
(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;
2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide;
2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide;
2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide;
2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide;
2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide;
2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;
2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;
(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;
1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piper-
idin-2-one; 1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;
1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;
1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;
1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepa-
n-2-one; 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one;
5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan--
2-one; 1-(1H-imidazol-5-ylmethyl)-5-phenylazepan-2-one;
5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan--
2-one; 1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one;
1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one;
4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;
2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide;
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H--
thieno[3,2-b]pyrrol-5-one;
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thi-
eno[3,2-b]pyrrol-5-one;
1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;
2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
2-(2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;
6-bromo-3-(2-oxopropyl)-1,3-benzothiazol-2(3H)-one;
2-(6-nitro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;
2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;
2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;
6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one;
1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one;
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide;
5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;
2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;
2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;
1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one;
2-(6-iodo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;
2-(6-cyano-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;
7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,-
5-tetrahydro-3H-2-benzazepin-3-one;
7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3--
one;
7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepi-
n-2-one;
7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl-
}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one;
1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]piperidin-2-one;
1-[(2-phenyl-1H-indol-1-yl)methyl]piperidin-2-one;
[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]cyanamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]acetamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]propanamide;
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanamide; and
N-[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]methanesu-
lfonamide.
[0390] The methods of the invention comprise administration to a
mammal (preferably human) suffering from above mentioned conditions
or disorders, of a compound according to the invention in an amount
sufficient to alleviate or prevent the disorder or condition.
[0391] The compound is conveniently administered in any suitable
unit dosage form, including but not limited to one containing 3 to
3000 mg, preferably 25 to 500 mg of active ingredient per unit
dosage form.
[0392] The term "treatment" as used herein includes curative
treatment and prophylactic treatment.
[0393] By "curative" is meant efficacy in treating a current
symptomatic episode of a disorder or condition.
[0394] By "prophylactic" is meant prevention of the occurrence or
recurrence of a disorder or condition.
[0395] The term "epilepsy" as used herein refers to a chronic
neurologic condition characterised by unprovoked, recurrent
epileptic seizures. An epileptic seizure is the manisfestation of
an abnormal and excessive synchronised discharge of a set of
cerebral neurons; its clinical manifestations are sudden and
transient. The term "epilepsy" as used herein can also refer to a
disorder of brain function characterised by the periodic occurrence
of seizures. Seizures can be "nonepileptic" when evoked in a normal
brain by conditions such as high fever or exposure to toxins or
"epileptic" when evoked without evident provocation.
[0396] The term "seizure" as used herein refers to a transient
alteration of behaviour due to the disordered, synchronous, and
rhythmic firing of populations of brain neurones.
[0397] The term "Parkinsonian symptoms" relates to a syndrome
characterised by slowlyness of movement (bradykinesia), rigidity
and/or tremor. Parkinsonian symptoms are seen in a variety of
conditions, most commonly in idiopathic parkinsonism (i.e.
Parkinson's Disease) but also following treatment of schizophrenia,
exposure to toxins/drugs and head injury. It is widely appreciated
that the primary pathology underlying Parkinson's disease is
degeneration, in the brain, of the dopaminergic projection from the
substantia nigra to the striatum. This has led to the widespread
use of dopamine-replacing agents (e.g. L-3,4-dihydroxyphenylalanine
(L-DOPA) and dopamine agonists) as symptomatic treatments for
Parkinson's disease and such treatments have been successful in
increasing the quality of life of patients suffering from
Parkinson's disease. However, dopamine-replacement treatments do
have limitations, especially following long-term treatment.
Problems can include a wearing-off of the anti-parkinsonian
efficacy of the treatment and the appearance of a range of
side-effects which manifest as abnormal involuntary movements, such
as dyskinesias.
[0398] The term "dyskinesia" is defined as the development in a
subject of abnormal involuntary movements. This appears in patients
with Huntington's disease, in Parkinson's disease patients exposed
to chronic dopamine replacement therapy, and in Schizophrenia
patients exposed to chronic treatment with neuroleptics.
Dyskinesias, as a whole, are characterised by the development in a
subject of abnormal involuntary movements. One way in which
dyskinesias may arise is as a side effect of dopamine replacement
therapy for parkinsonism or other basal ganglia-related movement
disorders.
[0399] The term "migraine" as used herein means a disorder
characterised by recurrent attacks of headache that vary widely in
intensity, frequency, and duration. The attacks are commonly
unilateral and are usually associated with anorexia, nausea,
vomiting, phonophobia, and/or photophobia. In some cases they are
preceded by, or associated with, neurological and mood
disturbances. Migraine headache may last from 4 hours to about 72
hours. The International Headache Society (IHS, 1988) classifies
migraine with aura (classical migraine) and migraine without aura
(common migraine) as the major types of migraine. Migraine with
aura consists of a headache phase preceded by characteristic
visual, sensory, speech, or motor symptoms. In the absence of such
symptoms, the headache is called migraine without aura.
[0400] The term "bipolar disorders" as used herein refers to those
disorders classified as Mood Disorders according to the Diagnostic
and Statistical Manual of Mental Disorders, 4th edition (Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV.TM.), American
Psychiatry Association, Washington, DC, 1994). Bipolar disorders
are generally characterised by spontaneously triggered repeated
(i.e. at least two) episodes in which the patient's
hyperexcitability, activity and mood are significantly disturbed,
this disturbance consisting on some occasions of an elevation of
mood and increased energy and activity (mania or hypomania), and in
other occasions a lowering of mood and decreased energy and
activity (depression). Bipolar disorders are separated into four
main categories in the DSM-IV (bipolar (I) disorder, bipolar II
disorder, cyclothymia, and bipolar disorders not otherwise
specified).
[0401] The term "manic episode", as used herein refers to a
distinct period during which there is an abnormally and
persistently elevated, expansive, or irritable mood with signs of
pressured speech and psychomotor agitation.
[0402] The term "hypomania", as used herein refers to a less
extreme manic episode, with lower grade of severity.
[0403] The term "major depressive episode", as used herein refers
to a period of at least 2 weeks during which there is either
depressed mood or the loss of interest or pleasure in nearly all
activities with signs of impaired concentration and psychomotor
retardation.
[0404] The term "mixed episode", as used herein refers to a period
of time (lasting at least 1 week) in which the criteria are met
both for a manic episode and for a major depressive episode nearly
every day.
[0405] The term "chronic pain" as used herein refers to the
condition gradually being recognised as a disease process distinct
from acute pain. Conventionally defined as pain that persists
beyond the normal time of healing, pain can also be considered
chronic at the point when the individual realises that the pain is
going to be a persistent part of their lives for the foreseeable
future. It is likely that a majority of chronic pain syndromes
involves a neuropathic component, which is usually harder to treat
than acute somatic pain.
[0406] The term "neuropathic pain" as used herein refers to pain
initiated by a pathological change in a nerve which signals the
presence of a noxious stimulus when no such recognisable stimulus
exists, giving rise to a false sensation of pain. In other words,
it appears that the pain system has been turned on and cannot turn
itself off.
[0407] The term "tics" refers to common and often disabling
neurological disorders. They are frequently associated with
behaviour difficulties, including obsessive-compulsive disorder,
attention deficit hyperactivity disorder and impulse control. Tics
are involuntary, sudden, rapid, repetitive, nonrhythmic stereotype
movements or vocalizations. Tics are manifested in a variety of
forms, with different durations and degrees of complexity. Simple
motor tics are brief rapid movements that often involve only one
muscle group. Complex motor tics are abrupt movements that involve
either a cluster of simple movements or a more coordinated sequence
of movements. Simple vocal tics include sounds such as grunting,
barking, yelping, and that clearing. Complex vocal tics include
syllables, phrases, repeating other people's words and repeating
one's own words.
[0408] The activity of the compounds of formula I, or their
pharmaceutically acceptable salts, as anticonvulsants may be
determined in the audiogenic seizure model. The objective of this
test is to evaluate the anticonvulsant potential of a compound by
means of audiogenic seizures induced in sound-susceptible mice, a
genetic animal model with reflex seizures. In this model of primary
generalised epilepsy, seizures are evoked without electrical or
chemical stimulation and the seizure types are, at least in part,
similar in their clinical phenomenology to seizures occurring in
man (Loscher W. & Schmidt D., Epilepsy Res. (1998), 2, 145-181;
Buchhalter J. R., Epilepsia (1993), 34, S31-S41).
[0409] An alternative assay indicative of potential anticonvulsant
activity is binding to levetiracetam binding site (LBS) as
hereinafter described. As set forth in U.S. patent applications
Ser. Nos. 10/308,163 and 60/430,372, LBS has been identified as
belonging to the family of SV2 proteins. As used herein reference
to "LBS" is to be understood as including reference to SV2.
[0410] Activity in any of the above-mentioned indications can of
course be determined by carrying out suitable clinical trials in a
manner known to a person skilled in the relevant art for the
particular indication and/or in the design of clinical trials in
general.
[0411] For treating diseases, compounds of formula (I) or their
pharmaceutically acceptable salts may be employed at an effective
daily dosage and administered in the form of a pharmaceutical
composition.
[0412] Therefore, another embodiment of the present invention
concerns a pharmaceutical composition comprising an effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof in combination with a pharmaceutically
acceptable diluent or carrier.
[0413] To prepare a pharmaceutical composition according to the
invention, one or more of the compounds of formula (I) or a
pharmaceutically acceptable salt thereof is intimately admixed with
a pharmaceutical diluent or carrier according to conventional
pharmaceutical compounding techniques known to the skilled
practitioner.
[0414] Suitable diluents and carriers may take a wide variety of
forms depending on the desired route of administration, e.g., oral,
rectal, parenteral or intranasal.
[0415] Pharmaceutical compositions comprising compounds according
to the invention can, for example, be administered orally,
parenterally, i.e., intravenously, intramuscularly or
subcutaneously, intrathecally, by inhalation or intranasally.
[0416] Pharmaceutical compositions suitable for oral administration
can be solids or liquids and can, for example, be in the form of
tablets, pills, dragees, gelatin capsules, solutions, syrups,
chewing-gums and the like.
[0417] To this end the active ingredient may be mixed with an inert
diluent or a non-toxic pharmaceutically acceptable carrier such as
starch or lactose. Optionally, these pharmaceutical compositions
can also contain a binder such as microcrystalline cellulose, gum
tragacanth or gelatine, a disintegrant such as alginic acid, a
lubricant such as magnesium stearate, a glidant such as colloidal
silicon dioxide, a sweetener such as sucrose or saccharin, or
colouring agents or a flavouring agent such as peppermint or methyl
salicylate.
[0418] The invention also contemplates compositions which can
release the active substance in a controlled manner. Pharmaceutical
compositions which can be used for parenteral administration are in
conventional form such as aqueous or oily solutions or suspensions
generally contained in ampoules, disposable syringes, glass or
plastics vials or infusion containers.
[0419] In addition to the active ingredient, these solutions or
suspensions can optionally also contain a sterile diluent such as
water for injection, a physiological saline solution, oils,
polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents, antibacterial agents such as benzyl alcohol,
antioxidants such as ascorbic acid or sodium bisulphite, chelating
agents such as ethylene diamine-tetra-acetic acid, buffers such as
acetates, citrates or phosphates and agents for adjusting the
osmolarity, such as sodium chloride or dextrose.
[0420] These pharmaceutical forms are prepared using methods which
are routinely used by pharmacists.
[0421] The amount of active ingredient in the pharmaceutical
compositions can fall within a wide range of concentrations and
depends on a variety of factors such as the patient's sex, age,
weight and medical condition, as well as on the method of
administration. Thus the quantity of compound of formula (I) in
compositions for oral administration is at least 0.5% by weight and
can be up to 80% by weight with respect to the total weight of the
composition.
[0422] In accordance with the invention it has also been found that
the compounds of formula (I) or the pharmaceutically acceptable
salts thereof can be administered alone or in combination with
other pharmaceutically active ingredients. Non-limiting examples of
such additional compounds which can be cited for use in combination
with the compounds according to the invention are antivirals,
antispastics (e.g. baclofen), antiemetics, antimanic mood
stabilizing agents, analgesics (e.g. aspirin, ibuprofen,
paracetamol), narcotic analgesics, topical anesthetics, opioid
analgesics, lithium salts, antidepressants (e.g. mianserin,
fluoxetine, trazodone), tricyclic antidepressants (e.g. imipramine,
desipramine), anticonvulsants (e.g. valproic acid, carbamazepine,
phenytoin), antipsychotics (e.g. risperidone, haloperidol),
neuroleptics, benzodiazepines (e.g. diazepam, clonazepam),
phenothiazines (e.g. chlorpromazine), calcium channel blockers,
amphetamine, clonidine, lidocaine, mexiletine, capsaicin, caffeine,
quetiapine, serotonin antagonists, .beta.-blockers,
antiarrhythmics, triptans, ergot derivatives and amantadine.
[0423] Of particular interest in accordance with the present
invention are combinations of at least one compound of formula (I)
or a pharmaceutically acceptable salt thereof and at least one
compound inducing neural inhibition mediated by GABA.sub.A
receptors. The compounds of formula (I) exhibit a potentiating
effect on the compounds inducing neural inhibition mediated by
GABA.sub.A receptors enabling, in many cases, effective treatment
of conditions and disorders under reduced risk of adverse
effects.
[0424] Examples of compounds inducing neural inhibition mediated by
GABA.sub.A receptors include the following: benzodiazepines,
barbiturates, steroids, and anticonvulsants such as valproate,
viagabatrine, tiagabine or pharmaceutical acceptable salts
thereof.
[0425] Benzodiazepines include the 1,4-benzodiazepines, such as
diazepam and clonazepam, and the 1,5-benzodiazepines, such as
clobazam. Preferred compound is clonazepam.
[0426] Barbiturates include phenobarbital and pentobarbital.
Preferred compound is phenobarbital.
[0427] Steroids include adrenocorticotropic hormones such as
tetracosactide acetate, etc.
[0428] Anticonvulsants include hydantoins (phenytoin, ethotoin,
etc), oxazolidines (trimethadione, etc.), succinimides
(ethosuximide, etc.), phenacemides (phenacemide, acetylpheneturide,
etc.), sulfonamides (sulthiame, acetoazolamide, etc.), aminobutyric
acids (e.g. gamma-amino-beta-hydroxybutyric acid, etc.), sodium
valproate and derivatives, carbamazepine and so on.
[0429] Preferred compounds include valproic acid, valpromide,
valproate pivoxil, sodium valproate, semi-sodium valproate,
divalproex, clonazepam, phenobarbital, vigabatrine, tiagabine,
amantadine.
[0430] For the preferred oral compositions, the daily dosage is in
the range 3 to 3000 milligrams (mg) of compounds of formula
(I).
[0431] In compositions for parenteral administration, the quantity
of compound of formula (I) present is at least 0.5% by weight and
can be up to 33% by weight with respect to the total weight of the
composition. For the preferred parenteral compositions, the dosage
unit is in the range 3 mg to 3000 mg of compounds of formula I.
[0432] The daily dose can fall within a wide range of dosage units
of compound of formula (I) and is generally in the range 3 to 3000
mg. However, it should be understood that the specific doses can be
adapted to particular cases depending on the individual
requirements, at the physician's discretion.
[0433] The LBS binding compounds provided by this invention and
labeled derivatives thereof may be useful as standards and reagents
in determining the ability of tested compounds (e.g., a potential
pharmaceutical) to bind to the LBS receptor.
[0434] Labeled derivatives of LBS ligands provided by this
invention may also be useful as radiotracers for positron emission
tomography (PET) imaging or for single photon emission computerized
tomography (SPECT).
[0435] The present invention therefore further provides labelled
ligands as tools to screen chemical libraries for the discovery of
potential pharmaceutical agents, in particular for treatment and
prevention of the conditions set forth herein, on the basis of more
potent binding to LBS/SV2 proteins, for localizing SV2 proteins in
tissues, and for characterizing purified SV2 proteins. SV2 proteins
include SV2A, SV2B, and SV2C whereby SV2A is the binding site for
the anti-seizure drug levetiracetam and its analogs. The SV2
isoforms SV2A, SV2B, or SV2C can be derived from tissues,
especially brain, from any mammal species, including human, rat or
mice. Alternately the isoforms may be cloned versions of any
mammalian species, including human, rat, and mice, heterologously
expressed and used for assays. The screening method comprises
exposing brain membranes, such as mammalian or human brain
membranes, or cell lines expressing SV2 proteins or fragments
thereof, especially SV2A, but including SV2B and SV2C, to a
putative agent and incubating the membranes or proteins or
fragments and the agent with labelled compound of formula I. The
method further comprises determining if the binding of the compound
of formula (I) to the protein is inhibited by the putative agent,
thereby identifying binding partners for the protein. Thus, the
screening assays enable the identification of new drugs or
compounds that interact with LBS/SV2. The present invention also
provides photoactivable ligands of SV2/LBS.
[0436] The labelled-ligands can also be used as tools to assess the
conformation state of SV2 proteins after solubilization,
purification and chromatography. The labelled-ligands may be
directly or indirectly labeled. Examples of suitable labels include
a radiolabel, such as .sup.3H, a fluorescent label, an enzyme,
europium, biotin and other conventional labels for assays of this
type.
[0437] Screening assays of the present invention include methods of
identifying agents or compounds that compete for binding to the LBS
(especially SV2A). Labelled compounds of formula (I) are useful in
the methods of the invention as probes in assays to screen for new
compounds or agents that bind to the LBS (especially SV2A). In such
assay embodiments, ligands can be used without modification or can
be modified in a variety of ways; for example, by labelling, such
as covalently or non-covalently joining a moiety which directly or
indirectly provides a detectable signal. In any of these assays,
the materials can be labelled either directly or indirectly.
Possibilities for direct labelling include label groups such as:
radiolabels including, but not limited to, [.sup.3H], [.sup.14C],
[.sup.32P], [.sup.35S] or [.sup.125I], enzymes such as peroxidase
and alkaline phosphatase, and fluorescent labels capable of
monitoring the change in fluorescence intensity, wavelength shift,
or fluorescence polarization, including, but not limited to,
fluorescein or rhodamine. Possibilities for indirect labelling
include biotinylation of one constituent followed by binding to
avidin coupled to one of the above label groups or the use of
anti-ligand antibodies. The compounds may also include spacers or
linkers in cases where the compounds are to be attached to a solid
support. To identify agents or compounds which compete or interact
with labelled ligands according to the invention for binding to the
LBS (especially SV2A), intact cells, cellular or membrane fragments
containing SV2A or the entire SV2 protein or a fragment comprising
the LBS of the SV2 protein can be used. The agent or compound may
be incubated with the cells, membranes, SV2 protein or fragment
prior to, at the same time as, or after incubation with
Levetiracetam or an analog or derivative thereof. Assays of the
invention may be modified or prepared in any available format,
including high-throughput screening (HTS) assays that monitor the
binding of Levetiracetam or the binding of derivatives or analogs
thereof to SV2 or to the LBS of the SV2 protein. In many drug
screening programs which test libraries of compounds, high
throughput assays are desirable in order to maximize the number of
compounds surveyed in a given period of time. Such screening assays
may use intact cells, cellular or membrane fragments containing SV2
as well as cell-free or membrane-free systems, such as may be
derived with purified or semi-purified proteins. The advantage of
the assay with membrane fragment containing SV2 or purified SV2
proteins and peptides is that the effects of cellular toxicity
and/or bioavailability of the test compound can be generally
ignored, the assay instead being focused primarily on the effect of
the drug on the molecular target as may be manifest in an
inhibition of, for instance, binding between two molecules. The
assay can be formulated to detect the ability of a test agent or
compound to inhibit binding of labeled ligand according to the
invention to SV2 or a fragment of SV2 comprising the LBS or of
Levetiracetam, or derivatives or analogs thereof, to SV2 or a
fragment of SV2 comprising the LBS. The inhibition of complex
formation may be detected by a variety of techniques such as
filtration assays, Flashplates (Perkin Elmer, scintillation
proximity assays (SPA, Amersham Biosciences). For high-throughput
screenings (HTS), scintillation proximity assay is a powerful
method which uses microspheres coated with biological membranes and
requires no separation or washing steps.
[0438] Labelled ligands are also useful for assessing the
conformational state of SV2 after solubilization, purification, and
chromatography. Moreover, the present invention provides
photoactivable versions of the ligands for labelling and detection
in biological samples. The photoactivable ligands may also be used
to localize and purify SV2 from tissues, isolated cells,
subcellular fractions and membranes. The photoactivable could also
be used for SV2 cross-linking and identification of binding domains
of LBS ligands.
EXAMPLES
[0439] The following examples are provided for illustrative
purposes. Unless specified otherwise in the examples,
characterization of the compounds is performed according to the
following methods:
[0440] NMR spectra are recorded on a BRUKER AC 250 Fourier
Transform NMR Spectrometer fitted with an Aspect 3000 computer and
a 5 mm .sup.1H/.sup.13C dual probehead or BRUKER DRX 400 FT NMR
fitted with a SG Indigo.sup.2 computer and a 5 mm inverse geometry
.sup.1H/.sup.13C/.sup.15N triple probehead. The compound is studied
in DMSO-d.sub.6 (or CDCl.sub.3) solution at a probe temperature of
313 K or 300 K and at a concentration of 20 mg/ml. The instrument
is locked on the deuterium signal of DMSO-d.sub.6 (or CDCl.sub.3).
Chemical shifts are given in ppm downfield from TMS taken as
internal standard.
[0441] HPLC analyses are performed using one of the following
systems:
[0442] an Agilent 1100 series HPLC system mounted with an INERTSIL
ODS 3 C18, DP 5 .mu.m, 250.times.4.6 mm column. The gradient ran
from 100% solvent A (acetonitrile, water, H.sub.3PO.sub.4
(5/95/0.001, v/v/v)) to 100% solvent B (acetonitrile, water,
H.sub.3PO.sub.4 (95/5/0.001, v/v/v)) in 6 min with a hold at 100% B
of 4 min. The flow rate is set at 2.5 ml/min. The chromatography is
carried out at 35.degree. C.
[0443] a HP 1090 series HPLC system mounted with a HPLC Waters
Symmetry C18, 250.times.4.6 mm column. The gradient ran from 100%
solvent A (MeOH, water, H.sub.3PO.sub.4 (15/85/0.001M, v/v/M)) to
100% solvent B (MeOH, water, H.sub.3PO.sub.4 (85/15/0.001 M,
v/v/M)) in 10 min with a hold at 100% B of 10 min. The flow rate is
set at 1 ml/min. The chromatography is carried out at 40.degree.
C.
[0444] Mass Spectrometric Measurements in LC/MS mode are Performed
as Follows:
[0445] HPLC Conditions
[0446] Analyses are performed using a WATERS Alliance HPLC system
mounted with an INERTSIL ODS 3, DP 5 .mu.m, 250.times.4.6 mm
column.
[0447] The gradient ran from 100% solvent A (acetonitrile, water,
TFA (10/90/0.1, v/v/v)) to 100% solvent B (acetonitrile, water, TFA
(90/10/0.1, v/v/v)) in 7 min with a hold at 100% B of 4 min. The
flow rate is set at 2.5 ml/min and a split of 1/25 is used just
before API source.
[0448] MS Conditions
[0449] Samples are dissolved in acetonitrile/water, 70/30, v/v at
the concentration of about 250 .mu.gr/ml. API spectra (+ or -) are
performed using a FINNIGAN (San Jose, Calif., USA) LCQ ion trap
mass spectrometer. APCI source operated at 450.degree. C. and the
capillary heater at 160.degree. C. ESI source operated at 3.5 kV
and the capillary heater at 210.degree. C.
[0450] Mass spectrometric measurements in DIP/EI mode are performed
as follows: samples are vaporized by heating the probe from
50.degree. C. to 250.degree. C. in 5 min. EI (Electron Impact)
spectra are recorded using a FINNIGAN (San Jose, Calif., USA) TSQ
700 tandem quadrupole mass spectrometer. The source temperature is
set at 150.degree. C.
[0451] Mass spectrometric measurements on a TSQ 700 tandem
quadrupole mass spectrometer (Finnigan MAT, San Jose, Calif., USA)
in GC/MS mode are performed with a gas chromatograph model 3400
(Varian, Walnut Creek, Calif., USA) fitted with a split/splitless
injector and a DB-5MS fused-silica column (15 m.times.0.25 mm I.D.,
1 .mu.m) from J&W Scientific (Folsom, Calif., USA). Helium
(purity 99.999%) is used as carrier gas. The injector (CTC A200S
autosampler) and the transfer line operate at 290 and 250.degree.
C., respectively. Sample (1 .mu.l) is injected in splitless mode
and the oven temperature is programmed as follows: 50.degree. C.
for 5 min., increasing to 280.degree. C. (23.degree. C./min) and
holding for 10 min. The TSQ 700 spectrometer operates in electron
impact (EI) or chemical ionization (Cl/CH.sub.4) mode (mass range
33-800, scan time 1.00 sec). The source temperature is set at
150.degree. C. Also used is a 1100 LCMSD VL series, single
quadrupole, APCI or API-ES ionization (Agilent Technologies, USA)
equipped with the following HPLC columns: Luna C18 5 um
100.times.4.6 mm (Phenomenex, USA) or Hi-Q C18 5 um 100.times.4.6
mm (Peeke Scientific, USA) or Betasil C18 10 um 150.times.4.6 mm
(ThermoHypersil, USA). GC/MS are also done with GC 6890 equipped
with FID and 5973 MSD, single quadrupole, EI ionization (Agilent
Technologies, USA) equipped with column: HP-5MS 30 m.times.0.25
mm.times.0.25 um (Agilent Technologies, USA).
[0452] Specific rotation is recorded on a Perkin-Elmer 341
polarimeter. The angle of rotation is recorded at 25.degree. C. on
1% solutions in MeOH. For some molecules, the solvent is
CH.sub.2Cl.sub.2 or DMSO, due to solubility problems.
[0453] Melting points are determined on a Buchi 535 or 545
Tottoli-type fusionometre, and are not corrected, or by the onset
temperature on a Perkin Elmer DSC 7.
[0454] Preparative chromatographic separations are performed on
silicagel 60 Merck, particle size 15-40 .mu.m, reference
1.15111.9025, using Novasep axial compression columns (80 mm i.d.),
flow rates between 70 and 150 ml/min. Amount of silicagel and
solvent mixtures as described in individual procedures.
[0455] Preparative Chiral Chromatographic separations are performed
on a DAICEL Chiralpak AD 20 .mu.m, 100*500 mm column using an
in-house build instrument with various mixtures of lower alcohols
and C5 to C8 linear, branched or cyclic alkanes at .+-.350 ml/min.
Solvent mixtures as described in individual procedures.
[0456] The following abbreviations are used in the examples:
[0457] AcOEt Ethyl acetate
[0458] CH.sub.3CN Acetonitrile
[0459] CH.sub.2Cl.sub.2 Dichloromethane
[0460] DCE 1,2-dichloroethane
[0461] DMF N,N-Dimethylformamide
[0462] MTBE Methyl tert-butyl ether
[0463] NBS N-bromosuccinimide
[0464] NCS N-chlorosuccinimide
[0465] NIS N-iodosuccinimide
[0466] TFA Trifluoroacetic acid
[0467] THF Tetrahydrofuran
[0468] The following examples illustrate how the compounds covered
by formula (I) may be obtained.
Example 1
Synthesis of
(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide 1 and
(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide 3
##STR00066##
[0469] 1.1 Synthesis of
(2S)-2-{[(benzylamino)acetyl]amino}butanamide a3
[0470] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, under inert atmosphere, triethylamine (69 mL, 496
mmol) is added dropwise to a solution of (benzylamino)acetic acid
a1 (50 g, 248 mmol) in a mixture of DMF (400 mL) and CHCl.sub.3
(400 mL) at 0.degree. C. The mixture is stirred at 0.degree. C. for
10 minutes and at room temperature for 15 minutes.
1H-1,2,3-benzotriazol-1-ol (36.9 g, 273 mmol),
(2S)-2-aminobutanamide a2 (30.4 g, 298 mmol) and
N,N'-dicyclohexylcarbodiimide (56.33 g, 273 mmol) are respectively
added to the mixture, each one of them in solution of 250 mL (or
300 mL) of CHCl.sub.3/DMF (50/50 v/v). DMF (200 mL) is added and
the mixture is heated at 45.degree. C. for 4 h, and stirred at room
temperature for 3 days. The mixture is partially concentrated (2/3
of solvent is removed) and again heated at 45.degree. C. overnight.
The whole solvent is removed under reduced pressure, the residue is
dissolved in CH.sub.2Cl.sub.2 and filtered. The organic phase is
concentrated, the obtained residue is purified by chromatography on
silicagel (CH.sub.2Cl.sub.2/C.sub.2H.sub.5OH/NH.sub.4OH 94/6/0.6
v/v/v) and recrystallized from AcOEt to afford
(2S)-2-{[(benzylamino)acetyl]amino}butanamide a3 (36.8 g). Yield:
58.9%.
[0471] .sup.1H NMR .delta..sub.H (250 MHz, DMSO, ppm): 0.85 (t,
3H), 1.5-1.8 (m, 2H), 2.7 (s, 1H), 3.15 (s, 2H), 3.7 (s, 2H), 4.25
(m, 1H), 7.0 (s, 1H), 7.2-7.5 (m, 6H), 7.9 (d, 1H).
1.2 Synthesis of (2S)-2-(3-benzyl-5-oxoimidazolidin-1-yl)butanamide
a4
[0472] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, a mixture of
(2S)-2-{[(benzylamino)acetyl]amino}butanamide a3 (36.8 g, 148 mmol)
and formaldehyde (91 mL, 37% in water) is heated at 78.degree. C.
for 1 hour and cooled down to room temperature. The mixture is
extracted by AcOEt (3.times.300 mL), the combined organic phases
are dried over MgSO.sub.4 and concentrated under reduced pressure.
The residue is purified twice by chromatography on silicagel
(eluent 1: CH.sub.2Cl.sub.2/C.sub.2H.sub.5OH/NH.sub.4OH 94/6/0.6
v/v/v; eluent 2: CH.sub.2Cl.sub.2/isopropanol/NH.sub.4OH 95/5/0.5
v/v/v) to afford (2S)-2-(3-benzyl-5-oxoimidazolidin-1-yl)butanamide
a4 (26.3 g). Yield: 68%. GC-MS (M.sup.+): 261.
1.3 Synthesis of (2S)-2-(5-oxoimidazolidin-1-yl)butanamide a5
[0473] In a 2 L pressured jar, under inert atmosphere,
(2S)-2-(3-benzyl-5-oxo-1-imidazolidinyl)-butanamide a4 (24.4 g, 93
mmol) is dissolved in ethanol (1 L). Pd/C (10%, 6.9 g, 30% wt) is
added and the mixture is hydrogenated on a Parr hydrogenator for
2.5 hours. The mixture is degassed, filtered on celite and the
filtrate is concentrated under reduced pressure. The crude residue
is purified by chromatography on silicagel
(CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH 88/12/1.2 v/v/v) to afford
15.48 g of (2S)-2-(5-oxoimidazolidin-1-yl)butanamide a5.
[0474] Yield: 97%.
[0475] .sup.1H NMR .delta..sub.H (250 MHz, DMSO+D.sub.2O, ppm):
0.85 (t, 3H), 1.5-1.9 (m, 2H), 3.3 (s, 2H), 4.25 (m, 2H), 4.45 (m,
1H), 6.9-7.4 (2 s (broad), 2.times.1H).
1.4 Synthesis of
(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide 1
[0476] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, (2S)-2-(5-oxoimidazolidin-1-yl)butanamide a5 (5
g, 29 mmol) and K.sub.2CO.sub.3 (4.04 g, 29 mmol) are dissolved in
DMSO (25 mL). A solution of 1-fluoro-4-nitrobenzene (4.2 g, 29
mmol) in DMSO (15 mL) is added dropwise and the mixture is heated
at 60.degree. C. overnight. The mixture is cooled to room
temperature, K.sub.2CO.sub.3 (0.81 g, 6 mmol) and
1-fluoro-4-nitrobenzene (0.84 g, 6 mmol, in 0.6 mL of DMSO) are
added. The mixture is heated again at 60.degree. C. for 3 hours, at
70.degree. C. for 75 minutes and concentrated under reduced
pressure. The crude reaction mixture is purified by chromatography
on silicagel (CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH 88/12/1.2
v/v/v) to afford 2.46 g of
(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide 1.
Yield: 29%. GC-MS (M.sup.+): 292.
1.5 Synthesis of
(2S)-2-[3-(4-aminophenyl)-5-oxoimidazolidin-1-yl]butanamide a6
[0477] In a Parr pressure jar, under inert atmosphere,
(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide 1 (1.79
g, 6.1 mmol) is dissolved in a mixture of methanol (180 mL) and
CHCl.sub.3 (10 mL). 10% Pd on charcoal (1 g, 55% wt) is added and
the mixture is hydrogenated under 40 psi for 2 hours. The mixture
is degassed and filtered on celite. The filtrate containing
(2S)-2-[3-(4-aminophenyl)-5-oxoimidazolidin-1-yl]butanamide a6 is
directly used in the next step.
1.6 Synthesis of (2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide
3
[0478] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, under inert atmosphere, the solution of
(2S)-2-[3-(4-aminophenyl)-5-oxoimidazolidin-1-yl]butanamide a6 in a
mixture of methanol/CHCl.sub.3 (95/5 v/v) obtained in step 1 (200
mL, 4.88 mmol) is cooled to 0.degree. C. Concentrated
H.sub.2SO.sub.4 (6 mL, 115 mmol) is added and NaNO.sub.2 (0.65 g,
9.76 mmol) is added carefully. The mixture is stirred at room
temperature for 1 hour and a solution of sodium hypophosphite
monohydrate (10.66 g, 97.6 mmol) in 80 mL of water is dropwise
added at 14.degree. C. After 10 minutes at 18.degree. C.,
CaSO.sub.4 is added and the mixture is stirred at room temperature
for 2 hours. The mixture is poured into 300 mL of cold water,
basified to pH 8.5 by the addition of NaOH 10% (w/w), and extracted
3 times with AcOEt. The combined extracts are dried over MgSO.sub.4
and concentrated under reduced pressure to give after purification
by chromatography on silicagel (CH.sub.2Cl.sub.2/i-PrOH/NH.sub.4OH
97/3/0.3 v/v/v) and recrystallization from EtOAc,
(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide 3 (0.365 g).
Yield: 30%. MS (dip-MS, M.sup.+): 247.
Example 2
Synthesis of
(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide
2
##STR00067##
[0480] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, under inert atmosphere,
(2S)-2-(5-oxoimidazolidin-1-yl)butanamide a5 (1 g, 5.84 mmol) is
dissolved in ethanol (10 mL). K.sub.2CO.sub.3 (0.81 g, 5.84 mmol)
is added and the mixture is cooled down to 0.degree. C. A solution
of 1-fluoro-2,4-dinitrobenzene (1.08 g, 5.84 mmol) in ethanol (2
mL) is added dropwise and the mixture is stirred overnight at room
temperature. The solvent is removed under reduced pressure, the
residue is purified by chromatography on silicagel
(CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH 96/4/0.4 v/v/v) and
recrystallized from acetonitrile to give
(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide 2
(1.148 g).
[0481] Yield: 58%. MS (dip-MS, MH.sup.+): 338.
Example 3
Synthesis of
(2S)-2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide 4
##STR00068##
[0482] 3.1 Synthesis of (2S)-2-(allylamino)butanamide a7
[0483] In a three necked flask fitted with a magnetic stirrer,
under inert atmosphere, (2S)-2-aminobutanamide a2 (30 g, 290 mmol)
is dissolved in DMF (300 mL) and K.sub.2CO.sub.3 (4 g, 29 mmol) is
added. The mixture is cooled to 0.degree. C. and allyl bromide (2.5
mL, 29 mmol) is added. After 1 h at 0.degree. C., the mixture is
concentrated and the residue is purified by chromatography on
silicagel (CH.sub.2Cl.sub.2/EtOH/NH.sub.4OH 97/2.7/0.3 v/v/v) to
give (2S)-2-(allylamino)butanamide a7 (4.1 g). Yield: 100%. LC-MS
(MH.sup.+): 143.
3.2 Synthesis of methyl allyl[1-(aminocarbonyl)propyl]carbamate
a8
[0484] In a three necked flask fitted with a magnetic stirrer,
under inert atmosphere, 2-(allylamino)butanamide a7 (3.73 g, 26.3
mmol) is dissolved in CH.sub.2Cl.sub.2 (40 mL). K.sub.2CO.sub.3 (4
g, 289.3 mmol) is added to the solution. The mixture is cooled to
0.degree. C. for the addition of methyl chloroformate (2.25 mL,
28.9 mmol). After stirring overnight at room temperature, the
solvent is removed under reduced pressure and the residue is
purified by chromatography on silicagel
(CH.sub.2Cl.sub.2/C.sub.2H.sub.5OH 95/5 v/v) to afford methyl
allyl[1-(aminocarbonyl)propyl]carbamate a8 (4.93 g). Yield: 94%.
GC-MS (M.sup.+): 200.
3.3 Synthesis of
(2S)-2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide 4
[0485] In a three necked flask fitted with a magnetic stirrer,
under inert atmosphere, methyl
allyl[1-(aminocarbonyl)propyl]carbamate a8 (4.69 g, 23.45 mmol) is
dissolved in CH.sub.2Cl.sub.2 (55 mL), KI (5.84 g, 35.18 mmol) and
1.sub.2 (17.87 g, 70.35 mmol) are added to the mixture. After
stirring at room temperature for 2 hours, the mixture is
concentrated and purified by chromatography on silicagel (the crude
solid is set down on the silicagel without dilution; tert-butyl
methyl ether/2-propanol 95/5 v/v), recrystallized from toluene and
ground up to obtain
(2S)-2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide 4 (0.7
g).
[0486] Yield: 9%. LC-MS (MH.sup.+): 313.
Example 4
Synthesis of (2S)-2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide
5
##STR00069##
[0487] 4.1 Synthesis of (2S)-2-(1H-pyrrol-1-yl)butanamide a9
[0488] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, under inert atmosphere, (2S)-2-aminobutanamide a2
(20.4 g, 190 mmol) is dissolved in 250 mL of acetic acid,
2,5-dimethoxytetrahydrofuran (25.5 g, 190 mmol) is added and the
mixture is brought to reflux for 45 minutes. The solvent is removed
under reduced pressure and the residue is purified by
chromatography on silicagel (CH.sub.2Cl.sub.2/i-PrOH 98/2 v/v) to
give (2S)-2-(1H-pyrrol-1-yl)butanamide a9 (13.76 g). Yield: 48%.
GC-MS (M.sup.+): 152.
4.2 Synthesis of
(2S)-2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide 5
[0489] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, under inert atmosphere,
(2S)-2-(1H-pyrrol-1-yl)butanamide a9 (8.61 g, 56.6 mmol) is
dissolved in CHCl.sub.3 (150 mL). K.sub.2CO.sub.3 (9.39 g, 67.9
mmol) is added to the mixture, and a solution of 4-chloroperbenzoic
acid (mCPBA, 25.5 g, 67.9 mmol) in CHCl.sub.3 (250 mL) is added
dropwise over 1.5 hours. The mixture is stirred at room temperature
for 6 hours. A solution of mCPBA (10.6 g, 28.2 mmol) in 100 mL of
CHCl.sub.3 is added twice (after 2.5 h and after 5 h). The mixture
is filtered and the precipitate is washed with CHCl.sub.3. The
filtrate is concentrated under reduced pressure. The residue is
purified by chromatography on silicagel
(CH.sub.2Cl.sub.2/C.sub.2H.sub.5OH 95/5 v/v), by preparative chiral
chromatography (column: Chiralpak AD 250*4.6 mm;
CH.sub.3OH/EtOH/isohexane 12/3/85 v/v/v) and recrystallized from
AcOEt to afford 0.302 g of
(2S)2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide 5.
[0490] Yield: 3%. GC-MS (M.sup.+): 168.
Example 5
Synthesis of
2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide 6
##STR00070##
[0491] 5.1 Synthesis of methyl 4-oxo-3-phenylbutanoate a11
[0492] In a 3 L three-necked flask fitted with a magnetic stirrer,
a Dean-Stark apparatus and a reflux condenser, phenylacetaldehyde
a10 (150 mL, 1150 mmol), toluene (750 mL) and diisobutylamine (202
mL, 1150 mmol) are heated at reflux for 2.5 h under inert
atmosphere. The mixture is concentrated to dryness and redissolved
in acetonitrile (300 mL). Methylbromoacetate (106 mL, 1150 mmol) is
added and the solution is heated at reflux for 4 h. At room
temperature, acetic acid (70 mL) and water (210 mL) are added and
the mixture is stirred for 0.5 h at room temperature and for 1 h at
45.degree. C. Acetonitrile is removed under reduced pressure and
the mixture is extracted with CH.sub.2Cl.sub.2. The organic phase
is washed with a saturated solution of NaHCO.sub.3, dried over
MgSO.sub.4 and concentrated in vacuo. The crude mixture is purified
by distillation under reduced pressure (110.degree. C., 0.5 mmHg)
to afford methyl 4-oxo-3-phenylbutanoate a11 (151.5 g) as a yellow
liquid.
[0493] Yield: 69%. LC-MS (MH.sup.+): 193.
5.2 Synthesis of methyl
4-{[(1S)-1-(aminocarbonyl)propyl]amino}-3-phenylbutanoate a12
[0494] In a 3 L three necked flask fitted with a mechanical stirrer
and a reflux condenser, under inert atmosphere, methyl
4-oxo-3-phenylbutanoate a11 (151.2 g, 790 mmol) is dissolved in
MeOH (1200 mL). Molecular sieves (3 A, 24 g) are added, followed by
(2S)-2-aminobutanamide (80.3 g, 790 mmol). The mixture is heated at
65.degree. C. for 1 h, cooled down to room temperature and
filtered. NaBH.sub.3CN (52.2 g, 790 mmol) is added, the temperature
raises to 45.degree. C. and the mixture is stirred at room
temperature for 2 h. A saturated solution of NH.sub.4Cl is added (1
L), the mixture is extracted with CH.sub.2Cl.sub.2, the organic
phase is dried over MgSO.sub.4 and concentrated to dryness under
reduce pressure. The crude reaction mixture is purified twice by
preparative chromatography on silicagel (eluent 1:
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 95/4.5/0.5 v/v/v; eluent 2:
CH.sub.2Cl.sub.2/hexane 50/50 v/v) to afford methyl
4-{[(1S)-1-(aminocarbonyl)propyl]amino}-3-phenylbutanoate a12 (101
g).Yield: 52%.
5.3 Synthesis of
2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide 6
[0495] Methyl
4-{[(1S)-1-(aminocarbonyl)propyl]amino}-3-phenylbutanoate a12 is
dissolved in acetic acid/MeOH (1/1 v/v) and heated at 80.degree. C.
for 2 h, cooled down to room temperature and concentrated under
reduce pressure. The obtained 1/1 diastereomeric mixture is
purified by chromatography on silicagel (CH.sub.2Cl.sub.2/i-PrOH
95/5 v/v) and by chiral chromatography (column: Chiralpack AD
250*4.6 mm; eluent: EtOH/diethylamine 100/0.1 v/v) to afford
(2S)-2-(2-oxo-4-phenyl-1-pyrrolidinyl)butanamide a13 (20.8 g), and
2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide 6 (1.19 g)
as secondary product. This compound is recrystallized from toluene
to give pure
(2S)-2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide 6
(0.87 g). Yield: 0.5%. LC-MS (MH.sup.+): 245.
Example 6
Synthesis of
(2S)-2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide 7
##STR00071##
[0497] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, under inert atmosphere,
(2S)-2-[4-(iodomethyl)-2-oxopyrrolidin-1-yl]butanamide a14 is
dissolved in DMF (50 mL) and
2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU, 1.9 mL,
12.65 mmol) is added. The mixture is heated at 90.degree. C. for 4
hours, cooled down to room temperature and concentrated. The crude
residue is purified twice by chromatography on silicagel (eluent 1:
gradient CH.sub.2Cl.sub.2/C.sub.2H.sub.5OH from 96/4 to 90/10 v/v;
eluent 2: gradient AcOEt/C.sub.2H.sub.5OH from 96/4 to 90/10 v/v)
to afford 0.260 g of
(2S)-2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide 7.
Yield: 12%. LC-MS (MH.sup.+): 191.
Example 7
Synthesis of
(+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide
8
##STR00072##
[0499] In a three neck flask, under argon,
5-hydroxy-4-propylfuran-2(5H)-one a15 (35.5 g, 0.25 mol) is added
to a solution of (2S)-2-aminobutanamide a2 (28.1 g, 0.275 mol) in
toluene (355 mL) at 18.degree. C. The solution is stirred for 0.5 h
at this temperature and a precipitate appears. The reaction mixture
is stirred for 2 h and 4 N NaOH (37.5 mL) is added dropwise to the
suspension followed by an aqueous solution of NaBH.sub.4 (6.2 g,
0.16 mol) in water (62 mL). After 1 h, the reaction mixture is
carefully quenched with AcOH (30 mL), heated to 50.degree. C. for 3
h and cooled down to room temperature overnight. NaOH is added (20
mL, 50% w/w) and the aqueous phase is extracted with toluene (2
times). The organic phases are combined, washed with brine and
concentrated under reduced pressure to afford the crude unsaturated
pyrrolidone (43.4 g) as an orange oil. It is recrystallized from
diisopropyl ether to afford
(+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide 8
as a white solid (1.8 g). Yield: 3.4%. LC-MS (MH.sup.+): 211.
Alpha.sub.D: +13.26.
Example 8
Synthesis of (2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide
9
##STR00073##
[0500] 8.1 Synthesis of S-(1-formylbutyl)O-methyl thiocarbonate
a17
[0501] In a three necked flask fitted with a magnetic stirrer,
under inert atmosphere, butyraldehyde a16 (1.89 g, 22 mmol) is
dissolved in CHCl.sub.3 (20 mL).
[0502] Methoxycarbonylsulfenyl chloride (2 mL, 22 mmol) is added
and the reaction mixture is stirred at room temperature overnight.
The mixture is concentrated and the residue is purified by
chromatography on silicagel (AcOEt/hexane 10:90) to afford 2.63 g
of S-(1-formylbutyl)-O-methyl thiocarbonate a17.
[0503] Yield: 68%. LC-MS (MH.sup.+): 177.
8.2 Synthesis of
(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide 9
[0504] In a three necked flask fitted with a magnetic stirrer,
under inert atmosphere, S-(1-formylbutyl)-O-methyl thiocarbonate
a17 (0.5 g, 2.8 mmol) and (2S)-2-aminobutanamide a2 (0.290 g, 2.8
mmol) are dissolved in toluene (5 mL). p-toluenesulfonyl chloride
(catalytic amount) is added and the mixture is heated to reflux for
1,5 hours. Acetic acid (1 mL) is added to the hot solution and the
mixture is concentrated under reduced pressure. The residue is
dissolved in AcOEt, washed with water and a saturated solution of
NaHCO.sub.3 The organic layer is dried over MgSO.sub.4, filtered
and concentrated under reduced pressure. The crude reaction mixture
is purified by chromatography on silicagel
(CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH 97/2.7/0.3 v/v/v). Crude 9
is triturated in Et.sub.2O to afford 0.4 g of pure
(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide 9. Yield:
63%. LC-MS (MH.sup.+): 229.
Example 9
Synthesis of 2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide
10
##STR00074##
[0505] 9.1 Synthesis of 2-amino-5-propyl-1,3-thiazol-4(5H)-one
a19
[0506] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, under nitrogen atmosphere, ethyl
2-bromopentanoate a18 (8.36 g, 40 mmol), thiourea (3.06 g, 40 mmol)
and sodium acetate (3.30 g, 40 mmol) are dissolved in 160 mL of
ethanol. The mixture is heated at 65.degree. C. for 2.5 hours. The
reaction mixture is cooled down to room temperature and partially
concentrated under reduced pressure. A saturated solution of
NaHCO.sub.3 is added to the white precipitate till neutral pH
(after the addition, the precipitate dissolves and precipitates
again). Et.sub.2O (65 mL) and hexane (65 mL) are added, the mixture
is stirred at room temperature for 0.5 h and the solid is filtered
to afford 2-amino-5-propyl-1,3-thiazol-4(5H)-one a19 (5.37 g) as a
white solid. Yield: 85%. LC-MS (MH.sup.+): 159.
9.2 Synthesis of 5-propyl-1,3-thiazolidine-2,4-dione a20
[0507] In a 500 mL flask, fitted with a magnetic stirrer and a
reflux condenser, 2-amino-5-propyl-1,3-thiazol-4(5H)-one a19 (5.37
g, 34 mmol) is dissolved in 90 mL of HCl (2.5 N) and 90 mL of
ethanol, and the mixture is heated at 65.degree. C. for 2.5 hours.
Several portions of 5 N HCl (5 mL) are added until complete
consumption of starting thiazolidinone. The reaction is cooled down
to room temperature. Saturated NaHCO.sub.3 is added until neutral
pH and the mixture is extracted with chloroform (3 times). The
combined organic extracts are dried over anhydrous MgSO.sub.4 and
concentrated under reduced pressure to afford a first fraction of
a20 (1.95 g) as an oil. The remaining aqueous phase is partially
concentrated, extracted with AcOEt (3 times), the combined organic
extracts are dried over MgSO.sub.4 and concentrated under reduced
pressure to afford a second batch of
5-propyl-1,3-thiazolidine-2,4-dione a20 (0.700 g) as a colorless
oil. Total yield: 49%. LC-MS (MH.sup.-): 158.
9.3 Synthesis of
2-(2,4-dioxo-5-propyl-1,3-thiazolidin-3-yl)propanamide a21
[0508] In a flask fitted with a magnetic stirrer and a reflux
condenser, under nitrogen atmosphere, a mixture of
5-propyl-1,3-thiazolidine-2,4-dione a20 (1.80 g, 11 mmol),
K.sub.2CO.sub.3 (1.545 g, 12.1 mmol), 2-bromopropionamide (1.698 g,
13.2 mmol) and DMF (36 mL) is heated to 35.degree. C. until
disappearance of starting material (6 days). Cold water is added
and the aqueous phase is extracted with AcOEt (3 times). The
combined organic extracts are washed with brine, dried over
anhydrous MgSO.sub.4 and concentrated under reduced pressure to
give 2-(2,4-dioxo-5-propyl-1,3-thiazolidin-3-yl)propanamide a21 as
a yellow oil which is used in the next step without further
purification. LC-MS (MH.sup.+): 231.
9.4 Synthesis of
2-(4-hydroxy-2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide
a22
[0509] In a flask fitted with a magnetic stirrer, under nitrogen
atmosphere, 2-(2,4-dioxo-5-propyl-1,3-thiazolidin-3-yl)propanamide
a21 is dissolved in methanol (9 mL). At 0.degree. C., NaBH.sub.4
(0.653 g, 22 mmol) is carefully added. The mixture is stirred at
0.degree. C. for 25 minutes and poured into cold water. The aqueous
phase is extracted with AcOEt (2.times.40 mL), the combined organic
extracts are dried over MgSO.sub.4 and concentrated under reduced
pressure to give crude
2-(4-hydroxy-2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide a22
which is used in the next step without further purification. LC-MS
(basic, MH.sup.+): 215 (2 diastereoisomers).
9.5 Synthesis of 2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide
10
[0510] In a one necked flask fitted with a magnetic stirrer and a
reflux condenser,
2-(4-hydroxy-2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide a22 is
dissolved in acetic acid (22 mL) and the solution refluxed
(80.degree. C.) for 3 hours. The mixture is left overnight at room
temperature. Water is added and acetic acid is removed in vacuo.
The mixture is neutralized by the addition of saturated NaHCO.sub.3
and extracted with AcOEt (3.times.80 mL). The combined organic
extracts are dried over MgSO.sub.4 and concentrated to give the
crude product which is purified by recrystallization from water to
afford 2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide 10 (0.257
g) as a white solid. Yield (3 steps): 14%. LC-MS (MH.sup.+):
215.
Example 10
Synthesis of 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide
15
##STR00075##
[0511] 10.1 Synthesis of cyano(phenyl)methyl
4-methylbenzenesulfonate a24
[0512] In a three necked flask fitted with a magnetic stirrer and a
dropping funnel, under inert atmosphere,
hydroxy(phenyl)acetonitrile a23 (2.4 mL, 20 mmol) is dissolved in
40 mL of CH.sub.2Cl.sub.2. The mixture is cooled down to
-10.degree. C. and triethylamine (5.87 mL, 40 mmol) is added. A
solution of p-toluenesulfonyl chloride (4.578 g, 24 mmol) in
CH.sub.2Cl.sub.2 (100 mL) is added dropwise while maintaining the
temperature under 0.degree. C. The mixture is stirred at 0.degree.
C. for 30 minutes and Et.sub.2O is added. The salts are filtered
and the filtrate is concentrated under reduced pressure to afford
crude cyano(phenyl)methyl 4-methylbenzenesulfonate a24 which is
directly used in the next step.
[0513] 1-cyanopentyl 4-methylbenzenesulfonate a25 may be
synthesized according to the same method.
10.2 Synthesis of S-[cyano(phenyl)methyl]ethanethioate a26
[0514] In a three necked flask fitted with a magnetic stirrer and a
dropping funnel, under inert atmosphere, cyano(phenyl)methyl
4-methylbenzenesulfonate a24 is dissolved in DMF (20 mL). A
solution of potassium thioacetate (2.512 g, 22 mmol) in DMF (20 mL)
is added dropwise at room temperature. After 3 h, the mixture is
poured into cold water and extracted with Et.sub.2O (2.times.50
mL). The combined organic extracts are washed with brine, dried
over anhydrous MgSO.sub.4 and concentrated under reduced pressure.
The crude reaction mixture is purified by chromatography on
silicagel (AcOEt/hexane 25/75 v/v) to afford 2.9 g of
S-[cyano(phenyl)methyl]ethanethioate a26 as a yellow solid.
[0515] Yield (from a23): 76%. GC-MS (M.sup.+): 191.
[0516] S-(1-cyanopentyl)ethanethioate a27 (LC-MS (MH.sup.+): 172)
may be synthesized according to the same method.
10.3 Synthesis of 2-amino-1-phenylethanethiol a28
[0517] In a three necked flask fitted with a magnetic stirrer and a
dropping funnel, under nitrogen,
S-[cyano(phenyl)methyl]ethanethioate a26 (11.934 g, 62.4 mmol) is
dissolved in 56 mL of dry THF (distilled over sodium). The mixture
is cooled to 0.degree. C. and BH.sub.3-THF complex (124.6 mL, 124.8
mmol, 1 M) is added dropwise. After stirring overnight at room
temperature, the mixture is cooled again to 0.degree. C. and
methanol (125 mL) is slowly added. The mixture is stirred for 10
minutes and concentrated to give the crude
2-amino-1-phenylethanethiol a28 which is directly used in the next
reaction.
[0518] 1-aminohexane-2-thiol a29 may be synthesized according to
the same method.
10.4 Synthesis of 5-phenyl-1,3-thiazolidin-2-one a30
[0519] In a flask fitted with a magnetic stirrer,
2-amino-1-phenylethanethiol a28 dissolved in 125 mL of
toluene/distilled water (50/50 v/v) is cooled down to 0.degree. C.
and K.sub.2CO.sub.3 (25.867 g, 187.2 mmol) is added. Phosgene
(70.51 mL, 124.8 mmol, as a solution 20% in toluene) is added
dropwise. After one hour at 0.degree. C., the mixture is extracted
with Et.sub.2O (3.times.60 mL), dried over anhydrous MgSO.sub.4,
concentrated under reduced pressure and purified by chromatography
on silicagel (AcOEt/hexane 25/75 v/v) to afford 2.16 g of
5-phenyl-1,3-thiazolidin-2-one a30. Yield: 19% (from a26). LC-MS
(MH.sup.+): 180.
[0520] 5-butyl-1,3-thiazolidin-2-one a31 (LC-MS basic (MH.sup.+):
160) and 5-propyl-1,3-thiazolidin-2-one a32 (GC-MS (M.sup.+): 145)
may be synthesized according to the same method.
10.5 Synthesis of 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide
15
[0521] In a three necked flask fitted with a magnetic stirrer and a
dropping funnel, under nitrogen atmosphere,
5-phenyl-1,3-thiazolidin-2-one a30 (0.984 g, 7.5 mmol) is dissolved
in DMF (6 mL). NaH (0.343 g, 8.6 mmol, 60% dispersion in oil) is
added by portions at 5.degree. C. After stirring for 25 minutes at
room temperature, 2-bromobutanamide (1.557 g, 9 mmol) is added by
portions and the mixture is stirred overnight. Ice and water are
added and the mixture is extracted with AcOEt (3.times.20 mL). The
combined organic extracts are dried over anhydrous MgSO.sub.4 and
concentrated under reduced pressure to give the crude reaction
mixture which is purified by chromatography on silicagel
(CH.sub.2Cl.sub.2/C.sub.2H.sub.5OH 97.5/2.5 v/v). After
recry-stallization from AcOEt/Hexane (70/30 v/v),
2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide 15 is obtained as
a white solid (0.435 g). Yield: 22%. LC-MS (MH.sup.+): 265.
Compounds 11, 12, 13, 14 and 16 may be synthesized according to the
same method.
Example 11
Synthesis of
(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide
17
##STR00076##
[0522] 11.1 Synthesis of
(2S)-2-[2-thioxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide
a34
[0523] In a flask fitted with a magnetic stirrer,
(2S)-2-[(4,4,4-trifluorobut-2-en-1-yl)amino]butan-amide a33
(synthesized as described in patent application WO 2005/121082; 5.0
g, 23.8 mmol) is dissolved in DMF (50 mL). Cs.sub.2CO.sub.3 (8.52
g, 26.2 mmol), nBu.sub.4NI (0.88 g, 2.38 mmol) and CS.sub.2 (2.2
mL, 35.7 mmol) are added and the reaction mixture is stirred at
room temperature for 1 hour. The salts are filtered and the
filtrate is concentrated under reduced pressure. The crude reaction
mixture is purified by chromatography on silicagel (AcOEt/hexane
50/50 v/v). The product is dissolved in CH.sub.2Cl.sub.2, the
organic phase is washed with water (2.times.50 mL), the organic
extract is dried over MgSO.sub.4 and the solvent is concentrated in
vacuo. The crude compound is purified successively by
chromatography on silicagel
(CH.sub.2Cl.sub.2/C.sub.2H.sub.5OH/NH.sub.4OH 97.08/2/0.2 v/v/v),
then by preparative HPLC on reverse phase (LC-prep-basic; column
30*50 mm xterra OBD 5 .mu.m; gradient:
CH.sub.3CN/H.sub.2O/hydrogenocarbonate) to afford 0.166 g of
(2S)-2-[2-thioxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide
a34. Yield: 2%. LC-MS (MH.sup.+): 287.
11.2 Synthesis of
(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide
17
[0524] In a flask fitted with a magnetic stirrer,
(2S)-2-[2-thioxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide
a34 (2.5 g, 8.7 mmol), benzoic acid (1.06 g, 8.7 mmol) and
benzyltriethylammonium chloride (0.198 g, 0.87 mmol) are dissolved
in CH.sub.2Cl.sub.2 (250 mL). A solution of KMnO.sub.4 (4.12 g,
26.1 mmol) in water (100 mL) is added. After vigorous stirring at
room temperature for 16 hours, Na.sub.2S.sub.2O.sub.5 is added to
the mixture until the color has disappeared. The mixture is
filtered and the aqueous phase is extracted with CH.sub.2Cl.sub.2.
The organic extracts are dried over MgSO.sub.4 and concentrated
under reduced pressure. The crude reaction mixture is purified
twice by chromatography on silicagel (eluent 1: hexane/AcOEt 70/30
v/v); eluent 2: CH.sub.2Cl.sub.2/C.sub.2H.sub.5OH/NH.sub.4OH
91.2/8/0.8 v/v/v) and recrystallized from diisopropyl ether to
afford
(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide
17 (0.267 g). Yield: 11%. LC-MS (MH.sup.+): 271.
Example 12
Synthesis of
1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piper-
idin-2-one 18
##STR00077##
[0525] 12.1 Synthesis of
6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine
a36
[0526] A solution of 6-chloro-3-aminopyridazine a35 (3.16 g, 24.2
mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (5 g, 24.4 mmol) in
1,2-dimethoxyethane (100 mL) is refluxed during 17 hours. After
cooling to room temperature and filtration, the solvent is removed
under reduced pressure and the crude reaction mixture is purified
by preparative chromatography on silicagel
(CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 98/2/0.2 v/v/v) to afford to
6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine a36.
Yield: 60%. LC-MS (MH.sup.+): 236/238.
12.2. Synthesis of
3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine
a37
[0527] A mixture of
6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine a36
(3.45 g, 1 eq, 14.64 mmol), N-bromosuccinimide (NBS; 2.87 g, 16.11
mmol) and azo-bis-iso-butyronitrile (AIBN; 240 mg, 1.5 mmol) in
acetonitrile (50 mL) is refluxed for 2 hours. After cooling to room
temperature, the solvent is removed under reduced pressure and the
crude product is purified by preparative chromatography on
silicagel (CH.sub.2Cl.sub.2) to afford
3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazi-
ne a37. Yield: 35%. LC-MS (MH.sup.+): 315/317.
12.3. Synthesis of
1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-pipe-
ridin-2-one 18
[0528] In a three-necked flask fitted with a magnetic stirrer, NaH
(60% in dispersion in mineral oil, 0.137 g, 3.4 mmol) is added to
THF (10 mL). A solution of piperidin-2-one (250 mg, 0.25 mmol) in
THF (5 mL) is added dropwise. A white solid appears and the mixture
is stirred for 10 min at room temperature. A solution of
3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine
a37 (0.720 g, 0.23 mmol) in THF (5 mL) is then added. After
stirring at room temperature for 24 h, H.sub.2O (10 mL) is added
and the reaction mixture is extracted with ethyl acetate and with
dichloromethane (twice). The combined organic phases are dried over
MgSO.sub.4, filtered and concentrated under reduced pressure.
[0529] The crude reaction mixture is purified by preparative
chromatography on silicagel (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH
98/1.8/0.2 v/v/v) and recrystallized from ethyl acetate to afford
1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piper-
idin-2-one 18 (0.248 g). Yield: 30%. LC-MS (MH.sup.+): 333/335.
[0530] Compound 29 may be synthesized according to the same
method.
Example 13
Synthesis of 1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one
22
##STR00078##
[0531] 13.1 Synthesis of 1-(hydroxymethyl)-5-phenylpiperidin-2-one
a39
[0532] KOH (9 mg, 0.16 mmol) is added to a suspension of
5-phenylpiperidin-2-one a38 (from Hill et al.; J. Am. Chem. Soc.
(1959), 81, 737; 1.75 g, 10 mmol) in absolute dioxane (2 mL) in the
absence of air moisture, and the reaction mixture is heated to
100-110.degree. C. Paraformaldehyde (0.325 g, 10.8 mmol) is added
in portions over 10 min. The formed homogeneous solution is stirred
at this temperature for 30 min and cooled down to room temperature.
The solvents are removed under reduced pressure, and the residue is
reevaporated with chloroform and then with diethylether to give 2.1
g of 1-(hydroxymethyl)-5-phenylpiperidin-2-one a39 as a semisolid
mass which is used in the next step without additional
purification. Yield: 100%.
[0533] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.97 (m, 3H), 2.37
(m, 2H), 3.07 (m, 1H), 4.69 (m, 1H), 4.77 (m, 1H), 5.77 (t, J=6.8
Hz, 1H), 7.25 (m, 1H), 7.32 (m, 5H).
[0534] The following compounds may be prepared according to the
same method:
TABLE-US-00001 a40 6-fluoro-3- GC-MS (M.sup.+): 183.
(hydroxymethyl)-1,3- benzoxazol-2(3H)-one a41 1-(hydroxymethyl)-5-
.sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 0.92 (m, 3 H),
propylpiperidin-2- 1.37 (m, 5 H), 1.85 (m, 2 H), onedroxymethyl)-5-
2.32-2.39 (m, 1 H), 2.41-2.51 (m, propylpiperidin-2-one 1 H), 3.08
(m, 1 H), 3.42-3.48 (m, 1 H), 4.74-4.96 (m, 2 H) a42
1-(hydroxymethyl)-4- .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.90
(m, phenylpiperidin-2-one 1 H), 2.03 (m, 1 H), 2.38 (m, 1 H), 2.47
(m, 1 H), 3.05 (m, 1 H), 3.42 (m, 2 H), 4.74 (s, 2 H), 5.79 (s, 1
H), 7.29 (m, 5 H) a43 1-(hydroxymethyl)-4- .sup.1H NMR
.delta..sub.H (DMSO, ppm): 0.87 (m, propylpiperidin-2-one 3 H),
1.19-1.40 (m, 5 H), 1.73 (m, 1 H), 1.86 (m, 1 H), 2.30 (m, 1 H),
3.30 (m, 3 H), 4.67 (m, 2 H), 5.69 (m, 1 H)
13.2 Synthesis of 1-(chloromethyl)-5-phenylpiperidin-2-one a44
[0535] SOCl.sub.2 (11.8 g, 100 mmol) is added in one portion to a
suspension of 1-(hydroxymethyl)-5-phenylpiperidin-2-one a39 (2.1 g,
10 mmol) in toluene (5 mL) at 0-5.degree. C. in the absence of air.
The homogeneous solution is stirred overnight allowing the mixture
to gradually heat to room temperature. The excess of SOCl.sub.2 and
toluene is removed, and the residue is reevaporated with
dichloromethane to give 1-(chloromethyl)-5-phenylpiperidin-2-one
a44 as a light-yellow oil that recrystallized on keeping is used in
the next step without additional purification.
[0536] .sup.1H NMR .delta..sub.H (DMSO, ppm): 2.09 (m, 2H), 2.53
(m, 1H), 2.65 (m, 1H), 3.13 (m, 1H), 3.59 (d, J=8.3 Hz, 2H), 5.16
(d, J=9.3 Hz, 1H), 5.49 (d, J=9.3 Hz, 1H), 7.27 (m, 3H), 7.35 (m,
2H).
[0537] The following compounds may be prepared according to the
same method:
TABLE-US-00002 a45 1-(chloromethyl)-5- .sup.1H NMR .delta..sub.H
(CDCl.sub.3, ppm): 0.94 (m, 3 H), propylpiperidin- 1.31-1.40 (m, 4
H), 1.47 (m, 1 H), 2-one 1.81-1.96 (m, 2 H), 2.36 (m, 1 H), 2.52
(m, 1 H), 3.14 (dd, J = 11.5, 10.3 Hz, 1 H), 3.43 (ddd, J = 11.7,
4.9, 2.0 Hz, 1 H), 5.14 (d, J = 9.3 Hz, 1 H), 5.44 (d, J = 9.3 Hz,
1 H) a46 1-(chloromethyl)- .sup.1H NMR .delta..sub.H (CDCl.sub.3,
ppm): 0.94 (m, 3 H), 5-propylpiperidin- 1.31-1.40 (m, 4 H), 1.47
(m, 1 H), 2-one 1.81-1.96 (m, 2 H), 2.36 (m, 1 H), 2.52 (m, 1 H),
3.14 (dd, J = 11.5, 10.3 Hz, 1 H), 3.43 (ddd, J = 11.7, 4.9, 2.0
Hz, 1 H), 5.14 (d, J = 9.3 Hz, 1 H), 5.44 (d, J = 9.3 Hz, 1 H) a47
1-(chloromethyl)- .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 2.06
(m, 1 H), 4-phenylpiperidin- 2.21 (m, 1 H), 2.56 (m, 1 H), 2.80 (m,
2-one 1 H), 3.14 (m, 1 H), 3.52 (m, 1 H), 3.61 (m, 1 H), 5.24 (d, J
= 9.3 Hz, 1 H), 7.20 (m, 2 H), 7.26 (m, 1 H), 7.35 (m, 2 H), 5.48
(d, J = 9.3 Hz, 1 H)
13.3 Synthesis of
1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one 22
[0538] Imidazole (0.272 g, 4.0 mmol) is added at 0-5.degree. C.
under argon to a suspension of LiH (0.160 g, 20 mmol) in absolute
DMF (22 mL). The mixture is stirred at this temperature for 45 min,
and a solution of 1-(chloromethyl)-5-phenylpiperidin-2-one a44
(1.07 g, 4.8 mmol) in absolute DMF (6 mL) is added. The reaction
mixture is stirred at 0-5.degree. C. for 1 h and at room
temperature for 1 h. The mixture is quenched with a saturated
NH.sub.4Cl solution (30 mL), diluted with water (30 mL), and
subjected to extraction with dichloromethane. The organic extract
is washed with water, dried over anhydrous Na.sub.2SO.sub.4, and
evaporated. The oily residue (1.06 g) is purified by chromatography
on silicagel (gradient AcOEt/MeOH from 20/1 to 10/1 v/v) to afford
1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one 22 as a viscous
oil (363 mg). Yield: 35%. LC-MS (MH.sup.+): 256.
[0539] Compounds 20 and 25 may be prepared according to the same
method.
[0540] Compounds 63 and 64 may be obtained using NaH instead of LiH
and at room temperature.
Example 14
Synthesis of
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one 21
##STR00079##
[0541] 14.1 Synthesis of 1-(pent-1-en-1-yl)piperidine a49
[0542] A solution of pentanal a48 (4.03 g, 47 mmol), piperidine
(3.99 g, 47 mmol) and 20 mg of pMePhSO.sub.3H in benzene (35 mL) is
refluxed with a Dean-Stark trap until water ceases to separate for
approximately 2.5 h. The solvents are removed under reduced
pressure to give 7.54 g of crude 1-(pent-1-en-1-yl)piperidine a49,
which is used in the next step without additional purification.
Yield: 100%.
[0543] .sup.1H NMR .delta..sub.H (DMSO, ppm): 0.84 (t, J=7.3 Hz,
3H), 1.28 (m, 2H), 1.46 (m, 6H), 1.87 (m, 2H), 2.68 (m, 4H), 4.24
(m, 1H), 5.78 (d, J=13.7 Hz, 1H).
14.2 Synthesis of ethyl 4-formylheptanoate a50
[0544] A solution of ethyl acrylate (5.88 g, 58.8 mmol) in absolute
acetonitrile (15 mL) is added dropwise under stirring in argon at
0-5.degree. C. to a solution of crude 1-(pent-1-en-1-yl)piperidine
a49 (7.54 g, 47 mmol) in absolute acetonitrile (35 mL) for 25 min.
In 1 h, the reaction mixture is heated to 75-80.degree. C., stirred
for 25 h, and a solution of acetic acid (3 mL) in water (20 mL) is
added. The reaction mixture is kept at 90.degree. C. for 8 h,
cooled to room temperature, saturated with NaCl and extracted with
diethylether. The combined organic extracts are sequentially washed
with 5% HCl, 5% NaHCO.sub.3, and brine, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated. The residue (6.26 g) is purified
by chromatography on silicagel (gradient hexane/AcOEt from 50/1 to
10/1 v/v) to give ethyl 4-formylheptanoate a50 (4.0 g). Yield:
46%.
[0545] .sup.1H NMR .delta..sub.H (DMSO, ppm): 0.92 (t, J=7.3 Hz,
3H), 1.24 (t, J=7.1 Hz, 3H), 1.29-1.48 (m, 3H), 1.65 (m, 1H), 1.77
(m, 1H), 1.95 (m, 1H), 2.22-2.40 (m, 3H), 4.12 (q, J=7.1 Hz, 2H),
9.58 (d, J=2.4 Hz, 1H).
14.3 Synthesis of ethyl
4-{[(tert-butoxycarbonyl)amino]methyl}heptanoate a51
[0546] A solution of ethyl 4-formylheptanoate a50 (3.68 g, 19.8
mmol), tert-butyl carbamate (6.74 g, 57.5 mmol), triethylsilane
(9.2 mL, 58 mmol), and TFA (3.05 mL, 38.3 mmol) in absolute
acetonitrile (86 mL) is stirred at room temperature under argon for
16 h. The reaction mixture is diluted with diethylether (180 mL),
washed with a 10% NaHCO.sub.3 solution, and the organic layer is
separated. The aqueous layer is additionally extracted with
diethylether (50 mL), and the combined organic extracts are washed
with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, and
evaporated. The residue (16.8 g) is purified by chromatography on
silicagel (hexane/AcOEt 10/1 v/v) to give ethyl
4-{[(tert-butoxycarbonyl)amino]methyl}-heptanoate a51 (3.57 g).
Yield: 62%.
[0547] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 0.88 (t, J=7.1
Hz, 3H), 1.23 (m, 5H), 1.31 (m, 2H), 1.43 (s, 9H), 1.47 (m, 1H),
1.60 (m, 2H), 2.32 (t, J=7.6 Hz, 2H), 2.96-3.16 (m, 2H), 4.11 (q,
J=7.1 Hz, 2H), 4.57 (m, 1H).
14.4 Synthesis of ethyl 4-(aminomethyl)heptanoate hydrochloride
a52
[0548] 4 N HCl in dioxane (20 mL, 80 mmol) is added to a solution
of ethyl 4-{[(tert-butoxycarbonyl)amino]methyl}heptanoate a51 (3.57
g, 12.4 mmol) in absolute dioxane (20 mL), and the reaction mixture
is stirred at room temperature overnight. The solvents are
evaporated under reduced pressure, and the residue (3.2 g) is
washed twice with hexane and reevaporated with diethylether to
afford 2.5 g of ethyl 4-(aminomethyl)heptanoate hydrochloride a52
as a colorless oil. Yield: 90%.
[0549] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 0.92 (t, J=6.6
Hz, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.35 (m, 4H), 1.78 (m, 3H), 2.37
(t, J=6.8 Hz, 2H), 2.95 (m, 2H), 4.12 (q, J=7.1 Hz, 2H), 8.36 (m,
3H).
14.5 Synthesis of
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one
trifluoroacetate 21
[0550] Triethylamine (0.27 mL, 1.95 mmol) is added to a solution of
ethyl 4-(aminomethyl)-heptanoate hydrochloride a52 (0.435 g, 1.95
mmol) in absolute Et.sub.2O (7 mL). The formed precipitate is
separated by filtration, and the filtrate is evaporated under
reduced pressure. The residue is dissolved in dichloromethane (3.6
mL), and imidazo[1,2-a]pyridine-3-carbaldehyde (0.284 g, 1.95 mmol)
and Ti(O-iPr).sub.4 (0.94 mL, 3.14 mmol) are added to the obtained
solution. The mixture is stirred at room temperature for 3 h, and
the solvents are removed under reduced pressure. The residue is
dissolved in absolute methanol (0.5 mL), and NaBH.sub.4 (0.116 g,
3.06 mmol) is added under stirring. After 15 min, the reaction
mixture is quenched by the addition of a 0.1 N NaOH solution (5
mL). The mixture is stirred for 10 min, diluted with
dichloromethane (20 mL), and passed through a Celite path. Celite
is washed with dichloromethane, and the filtrate is evaporated. The
residue (0.58 g) is subjected to rough purification by flash
chromatography on silicagel (chloroform/methanol 50/1 v/v) to give
a crude product. According to the .sup.1H NMR and LC-MS data, this
product consists of the mixture of compound 21, its non-cyclized
form (corresponding aminoester), and 5-propylvalerolactame. This
mixture is dissolved in toluene (3 mL) and refluxed for 4.5 h.
Toluene is removed under reduced pressure, and the residue is
purified by reverse phase HPLC (C18 column; gradient
acetonitrile/water/TFA from 20/80/0.1 to 85/15/0.1 v/v/v) to give
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one
trifluoroacetate 21 (0.149 g). Yield: 20%. LC-MS (MH.sup.+):
272.
[0551] Compound 19 may be obtained according to the same
method.
Example 15
Synthesis of
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one 23
##STR00080##
[0553] 1-imidazo[1,2-a]pyridin-3-ylmethanamine a54 (197 mg, 1.33
mmol) and Ti(O-i-Pr).sub.4 (0.713 mL, 2.37 mmol) are added to a
solution of ethyl 5-oxo-4-phenylpentanoate a53 (see Ledon H. et
al., Bull. Soc. Chim. Fr. (1973), 2071-2076; 294 mg, 1.33 mmol) in
dichloromethane (2.5 mL) under stirring in argon. The reaction
mixture is stirred at room temperature for 3.5 h, and an additional
portion of Ti(O-i-Pr).sub.4 (0.08 mL, 0.37 mmol) is added. After 40
min., the mixture is evaporated under reduced pressure. The residue
is dissolved in absolute methanol (6 mL), and NaBH.sub.4 (81 mg,
2.1 mmol) is added in portions under stirring. After 15 min., a 0.1
N NaOH solution (5 mL) is added, and the mixture is additionally
stirred for 15 min. and many times subjected to extraction with
dichloromethane. The combined organic extracts are dried over
anhydrous Na.sub.2SO.sub.4 and evaporated to afford an oily residue
(466 mg). According to the LC-MS data, this residue mainly
consisted of the mixture of methyl, ethyl, and isopropyl esters
a55. The residue is dissolved in toluene (10 mL) and refluxed for 9
h. The reaction mixture is cooled to room temperature and
evaporated under reduced pressure. The residue (459 mg) is purified
by chromatography on silicagel (chloroform/methanol 100/5 v/v) to
give crude compound 23 (purity of 72%; 285 mg), which is purified
several times by chromatography on silicagel (hexane/AcOEt 1/1 v/v)
to afford pure
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one 23
(110 mg).
[0554] Yield: 27%. LC-MS (MH.sup.+): 306.
Example 16
Synthesis of
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one
hydrochloride 24
##STR00081##
[0556] A mixture of ethyl 5-bromo-3-phenylpentanoate a56
(synthesized as described by Burger and Hofstetter in J. Org. Chem.
(1959), 24, 1290); 0.425 g, 1.49 mmol),
1-imidazo[1,2-a]pyridin-3-ylmethanamine a54 (0.329 g, 2.24 mmol),
and anhydrous Cs.sub.2CO.sub.3 (0.329 g, 2.24 mmol) in absolute
MeCN (6 mL) is refluxed under stirring in the absence of air
moisture for 5 h, cooled to room temperature, filtered, and
evaporated. The residue (0.57 g) is purified twice by
chromatography on silicagel (eluent 1: CHCl.sub.3/MeOH 20/1 v/v;
eluent 2: AcOEt/acetone 1/1 v/v). The obtained fraction is
dissolved in THF (0.5 mL) and 4 M HCl in dioxane (0.15 mL) is added
to the obtained solution to give, after filtration,
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one
hydrochloride 24 (0.082 g) as a solid.
[0557] Yield: 16%. LC-MS (MH.sup.+): 306.
[0558] 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one
hydrochloride 26 and
1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one 27 are
synthesized according to the same method, starting from ethyl
3-(2-bromoethyl)hexanoate a57 (synthesized in the racemic form
using a similar method to the one described by Jones J. B. and Lok
K. P. in Can. J. Chem. (1979), 57, 1025-1032).
Example 17
Synthesis of 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one 30,
1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one 33 and
1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one 34
##STR00082##
[0559] 17.1 Synthesis of tert-butyl
2-oxopropylazepane-1-carboxylates a59, a64 and a65
17.1.1 Synthesis of tert-butyl 2-oxo-5-propylazepane-1-carboxylate
a59
[0560] A solution of 5-propylazepan-2-one a58 (2.96 g, 19 mmol)
Boc.sub.2O (6.24 g, 28.6 mmol), and DMAP (2.55 g, 20.9 mmol) in
absolute THF (60 mL) is stirred in a flow of argon at room
temperature for 16 h. The reaction mixture is evaporated in vacuo.
The residue (9.4 g) is purified by flash-chromatography on
silicagel (chloroform). Tert-butyl
2-oxo-5-propyl-azepane-1-carboxylate a59 (4.50 g) is obtained as a
pale-yellow oil. Yield: 92.5%. LC-MS (MH.sup.+): 156.
[0561] Tert-butyl 2-oxo-5-phenylazepane-1-carboxylate a60 may be
synthesized according to the same method.
[0562] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.45 (s, 9H),
1.52-1.77 (m, 2H), 1.90 (m, 1H), 2.01 (m, 1H), 2.47 (m, 1H), 2.84
(m, 1H), 2.97 (m, 1H), 3.58 (m, 1H), 4.13 (m, 1H), 7.24 (m,
5H).
17.1.2 Synthesis of tert-butyl 2-oxo-4-propyl-1-azepanecarboxylate
a64 and tert-butyl 2-oxo-6-propyl-1-azepanecarboxylate a65
##STR00083##
[0563] (i) Synthesis of 4-propylazepan-2-one a62 and
6-propylazepan-2-one a63
[0564] 3-propylcyclohexanone a61 (1.0 g, 7.13 mmol; from H. O.
House, W. F. Fischer, J. Org. Chem. (1969), 34, 3615-3618) is
dissolved in chloroform (12.5 mL). Sodium azide (1.4 g, 21.4 mmol)
is added under stirring. After cooling to 0-5.degree. C. a solution
of methanesulfonic acid (6.85 g, 71.3 mmol) in chloroform (4.5 mL)
is added dropwise. The cooling bath is removed. The reaction
mixture is stirred for 3 h at room temperature. A saturated
solution of NaHCO.sub.3 is added to attain pH 7. The organic layer
is separated. The aqueous one is additionally extracted with
chloroform. The combined extracts are dried over anhydrous
MgSO.sub.4 and evaporated in vacuo. The residue is purified by
chromatography on silicagel (AcOEt) to afford a 0.70 g of a 1:1
mixture of regioisomers 4-propylazepan-2-one a62 and
6-propylazepan-2-one a63. Yield: 63%.
(ii) Synthesis of tert-butyl 2-oxo-4-propylazepane-1-carboxylate
a64 and tert-butyl 2-oxo-6-propylazepane-1-carboxylate a65
[0565] A solution of the mixture of regioisomers a62 and a63 (0.555
g, 3.57 mmol), DMAP (0.48 g, 3.93 mmol) and Boc.sub.2O (0.86 g,
3.93 mmol) in absolute THF (9 mL) is stirred at room temperature
for 48 h. The solvents are evaporated at room temperature. The
residue is purified by chromatography on silicagel (EtOAc/hexane
1:8) to afford of tert-butyl 2-oxo-4-propylazepane-1-carboxylate
a64 (0.36 g) and tert-butyl 2-oxo-6-propylazepane-1-carboxylate a65
(0.28 g).
[0566] Compound a64: Yield: 39.5%.
[0567] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 0.91 (t, J=7.1
Hz, 3H), 1.18-1.44 (m, 5H), 1.52 (s, 9H), 1.54-1.73 (m, 2H),
1.83-1.93 (m, 2H), 2.62 (m, 2H), 3.26 (m, 1H), 3.94 (m, 1H).
[0568] Compound a65: Yield: 30.5%.
[0569] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 0.89 (t, J=7.1
Hz, 3H), 1.24-1.40 (m, 5H), 1.52 (s, 9H), 1.54-1.63 (m, 1H),
1.69-1.79 (m, 1H), 1.83-1.95 (m, 2H), 2.54 (m, 2H), 3.46 (m, 1H),
4.65 (m, 1H).
17.2 Synthesis of methyl
4-{2-[(tert-butoxycarbonyl)amino]ethyl}heptanoate a66
[0570] Tert-butyl 2-oxo-5-propylazepane-1-carboxylate a59 (4.69 g,
18.4 mmol) is dissolved in absolute methanol (10 mL). A solution of
sodium methoxide (1.098 g, 20.3 mmol) in absolute methanol (13 mL)
is added under a flow of argon while stirring at 0-5.degree. C. for
15 min. The cooling bath is removed. The reaction mixture was
stirred at room temperature for 1 h, diluted with brine, and
extracted with diethylether. The organic layer is dried over
anhydrous Na.sub.2SO.sub.4 and evaporated to afford methyl
4-{2-[(tert-butoxycarbonyl)amino]-ethyl}heptanoate a66 (4.64 g) as
a pale-yellow oil. Yield: 88%. LC-MS (MH.sup.+): 288.
[0571] The following compounds may be prepared according to the
same method:
TABLE-US-00003 a67 methyl 6-[(tert- .sup.1H NMR .delta..sub.H
(DMSO, ppm): 1.35 (s, 9 H), butoxycarbonyl)- 1.59-1.79 (m, 3 H),
1.89 (m, 1 H), amino]-4- 2.07 (m, 2 H), 2.55 (m, 1 H), 2.73 (m, 2
H), phenylhexanoate 3.52 (s, 3 H), 6.71 (s (broad), 1 H), 7.18 (m,
2 H), 7.30 (m, 3 H) a68 methyl 5-{[(tert- .sup.1H NMR .delta..sub.H
(DMSO, ppm): 0.88 (m, 3 butoxycarbonyl)- H), 1.29 (m, 7 H), 1.44
(s, 9 H), 1.47 (m, amino]methyl}- 1 H), 1.87 (m, 1 H), 2.24 (m, 2
H), octanoate 3.09 (m, 2 H), 3.66 (s, 3 H). LC-MS (MH.sup.+): 288.
a69 methyl 6-[(tert- .sup.1H NMR .delta..sub.H (DMSO, ppm): 0.89
(m, 3 butoxycarbonyl)- H), 1.27 (m, 7 H), 1.44 (s, 9 H), 1.63 (m,
amino]-3- 2 H), 2.30 (m, 2 H), 3.06 (m, 2 H), propylhexanoate 3.67
(s, 3 H), 4.52 (s (broad), 1 H). LC-MS (MH.sup.+): 288.
17.3 Synthesis of methyl 4-(2-aminoethyl)heptanoate hydrochloride
a70
[0572] The reaction is carried out under anhydrous conditions.
Methyl 4-{2-[(tert-butoxycarbonyl)-amino]ethyl}heptanoate a66 (4.64
g, 16.0 mmol) is dissolved in absolute dioxane (15 mL). A 4 N
solution of HCl in dioxane (28 mL, 112 mmol) is added. The reaction
mixture is stirred at room temperature overnight. The solvents are
evaporated in vacuo. The residue is washed with hexane twice and
subjected to coevaporation with diethylether. Methyl
4-(2-aminoethyl)heptanoate hydrochloride a70 (3.95 g) is obtained
as a colorless oil. Yield: 98%. LC-MS (MH.sup.+): 188.
[0573] The following compounds may be prepared according to the
same method:
TABLE-US-00004 a71 methyl 6-amino- .sup.1H NMR .delta..sub.H (DMSO,
ppm): 1.74-1.96 (m, 4 4-phenylhexanoate H), 2.01-2.17 (m, 2 H),
2.44 (m, 1 H), 2.64 (m, 2 H), 3.53 (s, 3 H), 7.22 (m, 3 H), 7.31
(m, 2 H), 7.93 (s (broad), 3 H) a72 methyl 5- .sup.1H NMR
.delta..sub.H (DMSO, ppm): 0.85 (m, 3 H), (aminomethyl)- 1.17-1.34
(m, 6 H), 1.53 (m, 2 H), 1.77 (m, octanoate 1 H), 2.24 (m, 2 H),
2.72 (m, 2 H), hydrochloride 3.59 (s, 3 H), 7.94 (s (broad), 3H).
LC-MS (MH.sup.+): 188. a73 methyl 6-amino- .sup.1H NMR
.delta..sub.H (DMSO, ppm): 0.87 (m, 3 H), 3-propylhexanoate
1.17-1.34 (m, 6 H), 1.50 (m, 2 H), 1.63 (m, hydrochloride 1 H),
2.30 (m, 2 H), 2.67 (d, J = 6.36 Hz, 2 H), 3.59 (s, 3 H), 7.95 (s
(broad), 3 H). LC-MS (MH.sup.+): 188.
17.4 Synthesis of methyl
4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoate a75
[0574] Methyl 4-(2-aminoethyl)heptanoate hydrochloride a70 (0.447
g, 2.0 mmol) is suspended in absolute diethylether (2.5 mL). DIEA
(diisopropylethylamine) (0.35 mL, 2.0 mmol) is added, and after 5
min the resulting mixture is evaporated in vacuo. The residue is
dissolved in dichloromethane (2 mL). The obtained solution is added
to a preliminarily prepared solution of 4-formylimidazole (0.192 g,
2.0 mmol) and Ti(O-i-Pr).sub.4 (0.96 mL, 3.2 mmol) in
dichloromethane (5 mL). The reaction mixture is stirred at room
temperature for 3 h and evaporated in vacuo. The residue is
dissolved in absolute MeOH (5 mL). NaBH.sub.4 (0.114 g, 3.0 mmol)
is added under stirring. After 1 h the reaction mixture is diluted
with dichloro-methane (50 mL). The solution is washed with a
saturated solution of NaHCO.sub.3.
[0575] The aqueous layer is extracted with dichloromethane. The
combined extracts are dried over anhydrous Na.sub.2SO.sub.4 and
evaporated to afford methyl
4-{2-[(1H-imidazol-4-ylmethyl)amino]-ethyl}heptanoate a75 (0.498 g)
which is used in the next step without additional purification.
[0576] Yield: 93%. LC-MS: (MH.sup.+): 268.
[0577] The following compounds may be prepared according to the
same method:
TABLE-US-00005 a76 isopropyl 4-[2-({[2- .sup.1H NMR .delta..sub.H
(DMSO, ppm): 0.78 (m, 3 (trifluoromethyl)imidazo[1,2-a]pyridin-3-
H), 1.09 (m, 2 H), 1.13 (m, 7 H), yl]methyl}amino)ethyl]heptanoate
1.30 (m, 3 H), 1.40 (m, 2 H), 2.15 (m, 3 H), 2.46 (m, 2 H), 4.16
(s, 2 H), 4.84 (m, 1 H), 7.07 (m, 1 H), 7.43 (m, 1 H), 7.66 (m, 1
H), 8.58 (m, 1 H) a77 isopropyl 4-phenyl-6-({[2- .sup.1H NMR
.delta..sub.H (DMSO, ppm): 1.10 (d, J = 6.1, Hz,
(trifluoromethyl)imidazo[1,2-a]pyridin-3- 3 H), 1.12 (d, J = 6.3
Hz, 3 yl]methyl}amino)hexanoate H), 1.56-1.85 (m, 4 H), 1.95 (m, 2
H), 2.24 (m, 1 H), 2.34 (m, 1 H), 2.56 (m, 1 H), 4.10 (m, 2 H),
4.81 (m, 1 H), 7.0 (m, 2 H), 7.08-7.21 (m, 4 H), 7.45 (m, 1 H),
7.66 (m, 1 H), 8.55 (m, 1 H) a78 methyl 5-{[(1H-imidazol-4- LC-MS
(MH.sup.+): 268 ylmethyl)amino]methyl}octanoate a79 methyl
6-[(1H-imidazol-4-ylmethyl)amino]- LC-MS (MH.sup.+): 268
3-propylhexanoate
17.5 Synthesis of
4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoic acid
dihydrochloride a80
[0578] A solution of methyl
4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoate a75 (0.440 g,
1.65 mmol) in 6 N HCl (3 mL) is stirred at 50-55.degree. C. for 5.5
h. The reaction mixture is cooled to room temperature. The water is
evaporated in vacuo. The residue is vacuum-dried to afford 0.538 g
of crude 4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoic acid
dihydrochloride a80 (0.538 g). Yield: 100%. LC-MS: (MH.sup.+):
254.
[0579] The following compounds may be prepared according to the
same method:
TABLE-US-00006 a81
4-[2-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3- LC-MS
(MH.sup.+): 372 yl]methyl}amino)ethyl]heptanoic acid
dihydrochloride a82
4-phenyl-6-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3- LC-MS
(MH.sup.+): 406 yl]methyl}amino)hexanoic acid dihydrochloride a83
5-{[(1H-imidazol-4-ylmethyl)amino]methyl}octanoic acid LC-MS
(MH.sup.+): 254 dihydrochloride a84
6-[(1H-imidazol-4-ylmethyl)amino]-3-propylhexanoic acid LC-MS
(MH.sup.+): 254 dihydrochloride
17.6 Synthesis of 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one
30
[0580] The reaction is carried out under anhydrous conditions.
Crude 4-{2-[(1H-imidazol-4-ylmethyl)amino]ethyl}heptanoic acid
dihydrochloride a80 (0.538 g, 1.65 mmol) and DIEA (1.15 mm, 6.6
mmol) are dissolved in absolute DMF (100 mL), and TBTU
(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate) (0.582 g, 1.82 mmol) is added. The reaction
mixture is stirred at room temperature for 24 h and evaporated in
vacuo. The residue is purified by chromatography on alumina (150 g;
gradient CHCl.sub.3/MeOH from 50/1 to 10/1 v/v) and by
chromatography on silicagel (gradient EtOAc/MeOH from 10/1 to 4/1
v/v) affording pure 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one
30 (0.202 g). Yield: 52%. LC-MS (MH.sup.+): 236.
[0581] Compounds 31, 32, 33 and 34 may be prepared according to the
same method.
Example 18
Synthesis of
2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide 36
##STR00084##
[0582] 18.1 Synthesis of di-tert-butyl(3-nitro-2-thienyl)malonate
a86
[0583] In a one necked flask fitted with a magnetic stirrer, under
inert atmosphere, di(tert-butyl)malonate (10.53 g, 48.6 mmol) is
dissolved in DMSO (200 mL) and NaH (1.94 g, 48.6 mmol, 60%
dispersion in oil) is added at room temperature. The mixture is
heated up to 100.degree. C. for 1 hour to obtain a clear solution
then cooled down to 20.degree. C. and the 2-chloro-3-nitrothiophene
a85 (528 g, 32.4 mmol) is added in one portion. The red solution is
heated at 60.degree. C. for 2 hours. The mixture is cooled down and
water is slowly added. The mixture is diluted with
CH.sub.2Cl.sub.2, HCl (0.1M) is added until a yellow solution is
observed. The aqueous phase is extracted by CH.sub.2Cl.sub.2
(3.times.200 mL) and the combined organic extracts are dried over
anhydrous MgSO.sub.4 and concentrated under reduced pressure to
give a brown oil which is purified by chromatography on silicagel
(CH.sub.2Cl.sub.2/hexane 40/60 v/v) to afford
di-tert-butyl(3-nitro-2-thienyl)malonate a86 (6.1 g), which is
directly used in the next reaction.
[0584] Yield: 55%.
18.2 Synthesis of (3-nitro-2-thienyl)acetic acid a87
[0585] In a three necked flask fitted with a magnetic stirrer and a
reflux condenser, under nitrogen atmosphere,
di(tert-butyl)2-(3-nitro-2-thienyl)malonate a86 (6.1 g, 17.8 mmol)
is dissolved in TFA (50 mL) and the solution is brought to reflux
for 2 hours. The mixture is cooled down and the TFA is removed
under reduced pressure to give (3-nitro-2-thienyl)acetic acid a87
as a yellow solid (3.3 g). Yield: 100%. SM (DIP, M.sup.+): 187.
18.3 Synthesis of methyl(3-amino-2-thienyl)acetate a88
[0586] In a one necked flask fitted with a magnetic stirrer and a
reflux condenser, (3-nitro-2-thienyl)acetic acid a87 (3.3 g, 17.65
mmol) is dissolved in 25 mL of HCl (37% w/w)/CH.sub.3OH (1/1, v/v).
At room temperature, Sn (6.24 g, 52.95 mmol) is added in one
portion and the mixture is brought to reflux for 2 hours. After
stirring at room temperature for 10 hours, the mixture is
concentrated under reduced pressure to give a brown solid which is
dissolved in acetonitrile. Et.sub.3N (20 mL) is added and the
precipitate is filtered off. After concentration of the filtrate,
the residue is purified by chromatography on silicagel (gradient
CH.sub.2Cl.sub.2/ACOEt 100/0 to 0/100 v/v) to give
methyl(3-amino-2-thienyl)acetate a88 as a brown oil (2.7 g). Yield:
90%.
[0587] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 3.55-3.80 (m,
5H); 6.56-6.61 (d, 1H); 6.98-7.20 (d, 1H).
18.4 Synthesis of
2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide 36
[0588] In a sealed micro-wave tube,
methyl(3-amino-2-thienyl)acetate a88 (0.5 g, 2.92 mmol) is
dissolved THF (4 mL) and the mixture is submitted to 200 W at
100.degree. C. for 50 minutes. The solvent is removed and the
obtained crude product is first purified by chromatography on
silicagel (AcOEt), the by reverse phase HPLC (column C18 OBD 30*50
mm; gradient H.sub.2O/CH.sub.3CN/TFA v/v/v) to afford
2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide 36
(0.069 g) as brown solid. Yield: 12%. LC-MS (MH.sup.+): 197.
Example 19
Synthesis of
4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one
35
##STR00085##
[0589] 19.1 Synthesis of di-tert-butyl(3-amino-2-thienyl)malonate
a89
[0590] A solution of di-tert-butyl(3-nitro-2-thienyl)malonate a86
(343 mg, 1.0 mmol) in ethyl acetate (5 mL) is hydrogenated in a
Parr apparatus under a hydrogen pressure of 80 psi in the presence
of 10% Pd/C (34 mg) at room temperature for 24 h. the reaction
mixture is filtered through a Celite layer, and Celite is washed
with ethyl acetate. The combined filtrates are evaporated to afford
di-tert-butyl(3-amino-2-thienyl)malonate intermediate a89 as a
yellow oil (300 mg) with a purity of 90%. Yield: 95%.
[0591] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.42 (s, 18H),
4.81-4.86 (m, 3H), 6.49 (d, J=5.4 Hz, 1H), 7.15 (d, J=5.4 Hz,
1H).
19.2 Synthesis of
di-tert-butyl{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}malonate
a90
[0592] A mixture of di-tert-butyl(3-amino-2-thienyl)malonate a89
(1.0 g, 3.2 mmol) and 4-formylimidazole (0.306 g, 3.2 mmol) in
trimethyl orthoformate (16 mL) is stirred at room temperature for
20 h. Trimethyl orthoformate is evaporated under reduced pressure,
the residue is dissolved in methanol, and NaBH.sub.4 (0.243 g, 6.4
mmol) is added in portions.
[0593] Then the reaction mixture is stirred at room temperature for
16 h and evaporated to dryness. The residue is distributed between
water (10 mL) and chloroform (50 mL). The organic layer is
separated, dried over anhydrous Na.sub.2SO.sub.4, and evaporated.
The residue (1.49 g) is purified by chromatography on silicagel
(chloroform/methanol 10/1 v/v) to give di-tert-butyl
{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}malonate a90 (0.526
g). Yield: 42%.
[0594] .sup.1H NMR .delta..sub.H (DMSO, ppm)1.41 (s, 18H), 4.14 (d,
J=5.9 Hz, 2H), 4.91 (s, 1H), 6.74 (d, J=5.6 Hz, 1H), 6.83 (s, 1H),
7.23 (d, J=5.4 Hz, 1H), 7.53 (d, J=1.0 Hz, 1H), 11.82 (m, 1H).
19.3 Synthesis of
{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}acetic acid
dihydrochloride a91
[0595] A mixture of di-tert-butyl
{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}malonate a90 (0.52 g,
1.32 mmol) and 6 N HCl (9 mL) is stirred at 70-75.degree. C. for 45
min. The formed brown solution is cooled down to room temperature
and evaporated to dryness under reduced pressure. The residue is
several times reevaporated with benzene and vacuum-dried to give
crude {3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}acetic acid
dihydrochloride a91 (0.42 g) which is used as such in the next
step.
[0596] LC-MS (MH.sup.+): 236.
19.4 Synthesis of
4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one
35
[0597] DIEA (1.4 mL, 7.92 mmol) is added to a suspension of
{3-[(1H-imidazol-4-ylmethyl)amino]-2-thienyl}acetic acid
dihydrochloride a91 (0.42 g, 1.32 mmol) in dichloroethane (14 mL)
under stirring, and TBTU (0.466 g, 1.45 mmol) is added in 1 h. The
reaction mixture is stirred overnight, and the solvents are
evaporated. A 20% K.sub.2CO.sub.3 solution is added to the residue,
and the mixture is subjected to extraction with chloroform. The
combined extracts are dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue (0.61 g) is purified by chromatography on
silicagel (chloroform/methanol 10/1 v/v) to afford 0.125 g of
4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one
35. Yield: 43%.
[0598] LC-MS (MH.sup.+): 220.
Example 20
Synthesis of
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H--
thieno[3,2-b]pyrrol-5-one 37
##STR00086##
[0599] 20.1 Synthesis of
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methylene}amino)-2-th-
ienyl]acetic acid a92
[0600] A solution of
2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carbaldehyde (300 mg,
1.4 mmol) in dichloroethane (6 mL) is added under stirring to a
solution of di-tert-butyl(3-amino-2-thienyl)malonate a89 (220 mg,
0.7 mmol) in a mixture of dichloroethane/TFA (40 mL, 1/1), and
triethylsilane (0.455 mL, 2.8 mmol) is added in 10 min. The
reaction mixture is stirred at room temperature for 2 h, and
triethylsilane (0.215 mL, 1.2 mmol) is additionally added. The
mixture is stirred at 35-40.degree. C. for 3 h, and the solvents
are removed under reduced pressure. The solid residue is washed
with hexane and purified by chromatography on silicagel
(chloroform/methanol 10/1) to give 160 mg of
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methylene}amino)-2-th-
ienyl]acetic acid a92 with a purity of 85% (containing 15 wt %
[2-(trifluoromethypimidazo[1,2-a]pyridin-3-yl]methanol). Yield:
64%.
[0601] .sup.1H NMR .delta..sub.H (DMSO, ppm): 4.00 (s, 2H), 7.37
(td, J=6.8, 1.0 Hz, 1H), 7.45 (d, J=5.63 Hz, 1H), 7.52 (d, J=5.63
Hz, 1H), 7.72 (m, 1H), 7.94 (d, J=9.0 Hz, 1H), 8.93 (s, 1H), 9.94
(d, J=6.85 Hz, 1H).
20.2 Synthesis of
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)-2-thien-
yl]acetic acid a93
[0602] A mixture of
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methylene}amino)-2-th-
ienyl]acetic acid a92 (0.45 g, 1.27 mmol) and Na(CN)BH.sub.3 (0.180
g, 2.7 mmol) in absolute methanol (15 mL) is stirred for 18 h to
give crude intermediate a93 (0.38 g). Yield: 84%. LC-MS (MH.sup.+):
356.
20.3 Synthesis of
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H--
thieno[3,2-b]pyrrol-5-one 37
[0603] DIEA (1.4 mL, 7.92 mmol) is added to a suspension of
[3-({[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}amino)-2-thien-
yl]acetic acid a93 (0.42 g, 1.32 mmol) in dichloroethane (14 mL)
under stirring, and TBTU (0.466 g, 1.45 mmol) is added in 1 h. The
reaction mixture is stirred overnight, and the solvents are
evaporated. A 20% K.sub.2CO.sub.3 solution is added to the residue,
and the mixture is subjected to extraction with chloroform. The
combined extracts are dried over anhydrous Na.sub.2SO.sub.4 and
evaporated.
[0604] The residue (0.61 g) is purified by chromatography on
silicagel (chloroform/methanol 10/1) to afford 0.125 g of
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H--
thieno[3,2-b]pyrrol-5-one 37. Yield: 43%. LC-MS (MH.sup.+):
338.
Example 21
Synthesis of
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-hexahydro-5H-th-
ieno[3,2-b]pyrrol-5-one 38
##STR00087##
[0606] Na(CN)BH.sub.3 (54 mg, 0.88 mol) is added to a suspension of
[3-({[2-(trifluoromethyl)-imidazo[1,2-a]pyridin-3-yl]methylene}amino)-2-t-
hienyl]acetic acid a92 (155 mg, 0.43 mmol) in acetic acid (1.7 mL)
under stirring. After 5 min, a homogenous solution is formed, which
is stirred at room temperature overnight. Water is added to the
reaction mixture, which is evaporated to dryness, and a saturated
NaHCO.sub.3 solution (1 mL) is added to the residue.
[0607] The mixture is subjected to extraction with ethyl acetate,
and the organic extract is dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue (186 mg) is purified by chromatography
on silicagel (CCl.sub.4/AcOEt 1/1 v/v) to give a mixture of desired
compound with
[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methanol (51 mg) in
a molar ratio 1/1 according to the .sup.1H NMR data. A second
purification on silicagel (CHCl.sub.3/MeOH 100/5 v/v) affords 35 mg
of
4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thi-
eno[3,2-b]pyrrol-5-one 38 as a white crystalline substance. Yield:
23%. LC-MS (MH.sup.+): 342.
Example 22
Synthesis of
1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one 39
##STR00088##
[0608] 22.1 Synthesis of
ethyl{4-[(tert-butoxycarbonyl)amino]-3-thienyl}acetate a95
[0609] Triethylamine (0.92 mL, 6.6 mmol) is added under stirring in
argon to a suspension of
4-(2-ethoxy-2-oxoethyl)thiophene-3-carboxylic acid a94 (Ames D. E.,
Ribeiro O., Journal of the Chemical Society, Perkin Transactions 1
(1975), 14, 1390-51; 29 g, 6.0 mmol) in absolute tert-butanol (25
mL), and diphenyl azidophosphate is added to the formed homogeneous
solution. The reaction mixture is stirred at room temperature for 5
min and then under reflux for 16 h. Then the mixture is cooled to
room temperature and evaporated under reduced pressure. The residue
is dissolved in dichloromethane (50 mL), and the solution is washed
with 10% citric acid, a 10% NaHCO.sub.3 solution and brine, dried
over anhydrous Na.sub.2SO.sub.4, and evaporated. The oily residue
(2.2 g) is purified by chromatography on silicagel (gradient
CCl.sub.4/CHCl.sub.3 from 1/1 to 2/3 v/v) to afford
ethyl{4-[(tert-butoxycarbonyl)amino]-3-thienyl}acetate a95 as a
viscous oil (1.30 g). Yield: 76%.
[0610] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.19 (t, J=7.1 Hz,
3H), 1.46 (s, 9H), 3.66 (s, 2H), 4.07 (q, J=7.1 Hz, 2H), 7.23 (d,
J=3.4 Hz, 1H), 7.29 (s, 1H), 8.74 (s, 1H).
22.2 Synthesis of ethyl(4-amino-3-thienyl)acetate hydrochloride
a96
[0611] 4 M HCl in dioxane (8 mL, 31.8 mmol) is added under stirring
in the absence of air moisture to a solution of intermediate a95
(1.30 g, 4.55 mmol) in absolute dioxane (12 mL), and the mixture
stirred at room temperature for 24 h. The reaction mixture is
diluted with absolute diethylether (50 mL) and stirred for 1 h. The
formed precipitate is separated by filtration, washed with
diethylether, and dried in a vacuum dessicator over NaOH to give
ethyl(4-amino-3-thienyl)acetate hydrochloride a96 as a white powder
(0.84 g). Yield: 83%.
[0612] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.22 (t, J=7.1 Hz,
3H), 3.80 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 7.50 (m, 2H), 10.19 (m,
3H).
22.3 Synthesis of
ethyl{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate a97
[0613] A solution of 1H-imidazole-4-carbaldehyde a74 (0.613 g, 6.38
mmol) in CH.sub.2Cl.sub.2 (4 mL) is added under stirring in argon
to a solution of ethyl(4-amino-3-thienyl)acetate hydrochloride a96
(0.707 g, 3.19 mmol) in a mixture of CH.sub.2Cl.sub.2 (16 mL) and
TFA (16 mL). After 10 min, Et.sub.3SiH (1.0 mL, 6.38 mmol) is
added, and after 1 h Et.sub.3SiH (0.25 mL, 1.6 mmol) is
additionally added. The reaction mixture is stirred at room
temperature for 18 h, and the solvents are removed under reduced
pressure. The residue is treated with a 30% K2CO.sub.3 solution,
and the mixture is subjected to extraction with ethyl acetate
(3.times.75 mL). The combined organic extracts are dried over
anhydrous Na.sub.2SO.sub.4 and evaporated. The residue is purified
by chromatography on silicagel (CHCl.sub.3/MeOH 95/5 v/v) to give
ethyl{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate a97 as a
light-yellow viscous mass (0.25 g).
[0614] Yield: 30%.
[0615] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 1.24 (t, J=7.1
Hz, 3H), 3.52 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 4.29 (s, 2H), 6.05
(d, J=3.2 Hz, 1H), 7.01 (m, 2H), 7.63 (s, 1H).
22.4 Synthesis of sodium
{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate a98
[0616] NaOH (0.030 g, 0.70 mmol) is added under stirring in argon
to a solution of
ethyl{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate a97
(0.170 g, 0.64 mmol) in ethanol (0.9 mL). The mixture is stirred at
room temperature for 2.5 h, and ethanol is removed under reduced
pressure. The residue is triturated with acetonitrile and twice
reevaporated with acetonitrile to give crude sodium
{4-[(1H-imidazol-4-ylmethyl)amino]-3-thienyl}acetate a98 (0.16 g),
which is used in the next step without additional purification.
22.5 Synthesis of
1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one 39
[0617] TBTU (0.225 g, 0.70 mmol) is added in one portion under
stirring in argon to a suspension of crude sodium salt a98 (0.16 g,
0.64 mmol) in absolute MeCN (10 mL), and DIEA (2.0 mL) is added in
15 min. The reaction mixture is additionally stirred at room
temperature for 5 min and at 50-55.degree. C. for 5 h. The mixture
is cooled to room temperature, and the solvents are removed under
reduced pressure. The residue (0.40 g) is purified by
chromatography on silicagel (chloroform/methanol 95/5 v/v) to give
1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one 39
(0.075 g). Yield: 53%. LC-MS (MH.sup.+): 220.
Example 23
Synthesis of 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide
enantiomers 46 and 47
##STR00089##
[0619] In a 100 mL three necked flask fitted with a magnetic
stirrer, under inert atmosphere, 6-bromo-1,3-benzothiazol-2(3H)-one
a99 (5.218 g, 22.7 mmol) is dissolved in DMF (40 mL). The solution
is cooled to 0.degree. C. and NaH (1.176 g, 29.5 mmol, 60%
dispersion in oil) is carefully added. The mixture is stirred at
room temperature for 20 minutes, cooled again to 0.degree. C. and
2-bromopropionamide is added portionwise. After stirring overnight
at room temperature, the mixture is poured into cold water, the
solid is filtered off and washed with water and hexane.
2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide is obtained
as a white solid (6.31 g). Yield: 96%. GC-MS (M.sup.30 ):
300/302.
[0620] This compound is resolved into its enantiomers by chiral
chromatography (chiralcel OD 250*4.6 mm, eluent: EtOH/isohexane/DEA
50/50/0.1 v/v/v) to afford enantiomers 46 (first eluted, 1.829 g)
and 47 (second eluted,1.866 g) as, after trituration in hexane,
white solids.
[0621] Compound 46: Yield: 27%. GC-MS (M.sup.+): 300/302.
[0622] Compound 47: Yield: 27%. GC-MS (M.sup.+): 300/302.
[0623] Compounds 41 and 45 may be synthesized according to the same
method.
Example 24
Synthesis of 2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide
49
##STR00090##
[0625] In a 50 mL three necked flask fitted with a magnetic stirrer
and a reflux condenser, under inert atmosphere, KOH (0.763 g, 11.2
mmol) is added to a solution of 6-methyl-1,3-benzothiazol-2(3H)-one
a100 (1.85 g, 11.2 mmol) in acetone (13 mL). The mixture is brought
to reflux for 6 hours and cooled down slowly to 20.degree. C.
Distilled water (40 mL) is added, the mixture is stirred at room
temperature for 30 minutes, filtered and the filtrate is washed
with cold water to afford
2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)yl)acetamide 49 (2.267 g)
as a white solid. Yield: 91%. GC-MS (MH.sup.+): 222.
[0626] 2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)yl)acetamide 48 may
be synthesized according to the same method.
Example 25
Synthesis of 2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide
42
##STR00091##
[0628] In a 100 mL flask with a magnetic stirrer,
2-(2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide 41 (3.43 g, 16.5 mmol)
is dissolved in 20 mL of 90% H.sub.2SO.sub.4. The mixture is cooled
down to 0.degree. C. and N-chlorosuccinimide (2.12 g, 16.6 mmol) is
added portionwise. The mixture is stirred at room temperature for
25 minutes, poured into cold water and the solid is filtered off,
washed with cold water until the pH of the mother liquid exceeds 4
and recrystallized from EtOH/H.sub.2O (75/25 v/v) to afford
2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide 42 (1.20 g).
Yield: 30%. LC-MS (MH.sup.+): 243/245.
[0629] Compounds 40 and 44 may be synthesized according to the same
method, using N-bromosuccinimide instead of
N-chlorosuccinimide.
Example 26
Synthesis of
6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one
43
##STR00092##
[0630] 26.1 Synthesis of
6-bromo-3-(hydroxymethyl)-1,3-benzothiazol-2(3H)-one a101
[0631] In a 100 mL three necked flask fitted with a magnetic
stirrer and a reflux condenser, 6-bromo-1,3-benzothiazol-2(3H)-one
a99 (3 g, 13 mmol) and formaldehyde 35% (5 mL), are mixed in 20 mL
of methanol and 10 mL of water. The mixture is brought to reflux
for 4 hours and cooled down slowly to 20.degree. C. The reaction
mixture is filtered to afford
6-bromo-3-(hydroxymethyl)-1,3-benzothiazol-2(3H)-one a101 as white
solid (3.37 g) which is used in the next step without any further
purification. Yield: 100%. LC-MS (MH.sup.+): 229/231.
26.2 Synthesis of
6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one
43
[0632] In a 250 mL three necked flask fitted with a magnetic
stirrer and a reflux condenser,
6-bromo-3-(hydroxymethyl)-1,3-benzothiazol-2(3H)-one a101 (2.60 g,
10 mmol) is dissolved in acetonitrile (100 mL) and
1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole (2.43 g, 15 mmol) is
added in one portion. The mixture is brought to reflux for one
night and concentrated in vacuo to give the crude
6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one which
is purified by chromatography on silicagel
(CH.sub.2Cl.sub.2/EtOH/NH.sub.4OH 95/4.5/0.5 v/v/v) to give, after
recrystallization from ethanol,
6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one 43 as
white solid (0.813 g). Yield: 26%. LC-MS (MH.sup.+): 310/312.
[0633] Compound 50 may be prepared according to the same method
(from 6-fluoro-3-(hydroxymethyl)-1,3-benzoxazol-2(3H)-one a40).
Example 27
Synthesis of
1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one 51
##STR00093##
[0634] 27.1 Synthesis of
(3-ethoxy-3-oxopropanoyl)(pyridinium-1-yl)azanide a103
[0635] A mixture of 1-aminopyridinium iodide a102 (3.0 g, 13.5
mmol), diethyl malonate (18 mL, 119 mmol) and anhydrous
K.sub.2CO.sub.3 (22.5 g, 163 mmol) in absolute ethanol (225 mL) is
stirred at room temperature for 3 days. The reaction mixture is
filtered and the filtrate is evaporated. The residue is purified by
chromatography on basic aluminum oxide (gradient 1:
ether/chloroform from 100/0 to 0/100 v/v; gradient 2:
chloroform/methanol from 20/0 to 20/1 v/v). According to the
.sup.1H NMR data, the obtained fraction (2.68 g) is the mixture of
intermediate a103 with ethyl malonate in a molar ratio 1:1. This
fraction is washed several times with hexane until disappearance of
ethylmalonate to afford pure
(3-ethoxy-3-oxopropanoyl)(pyridinium-1-yl)azanide a103 (1.41 g).
Yield: 49%.
[0636] .sup.1H NMR .delta..sub.H (DMSO, ppm): 5.11 (s, 1H), 5.21
(s, 2H), 6.52 (m, 1H), 7.02 (s, 1H), 7.15 (m, 2H), 7.56 (s, 1H),
8.48 (d, J=6.5 Hz, 1H), 12.02 (m, 1H).
27.2 Synthesis of ethyl
2-oxo-1-[(1-trityl-1H-imidazol-4-yl)methyl]-1,2-dihydropyrazolo[1,5-a]pyr-
idine-3-carboxylate-methanol (1:2) a106
[0637] A mixture of
(3-ethoxy-3-oxopropanoyl)(pyridinium-1-yl)azanide a103 (0.52 g,
2.48 mmol) and 4-(chloromethyl)-1-trityl-1H-imidazole a104 (0.83 g,
2.31 mmol) in dry acetone (9 mL) is refluxed under argon for 4
days. Acetone is removed under reduced pressure, and the residue,
which contains not isolated intermediate
1-{(3-ethoxy-3-oxopropanoyl)[(1-trityl-1H-imidazol-4-yl)methyl]amino}pyri-
dinium chloride a105, is dissolved in absolute ethanol (9 mL).
Anhydrous K.sub.2CO.sub.3 (0.8 g, 5.80 mmol) is added, and the
mixture is stirred under reflux for 42 h. The reaction mixture is
cooled to room temperature, filtered and evaporated. The residue
(1.5 g) is purified by chromatography on silicagel (gradient
CHCl.sub.3/MeOH from 50/1 to 10/1 v/v) to afford 0.170 g of ethyl
2-oxo-1-[(1-trityl-1H-imidazol-4-yl)methyl]-1,2-dihydropyrazolo[1,5-a]pyr-
idine-3-carboxylate-methanol (1:2) a106. Yield: 14%.
[0638] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.26 (t, J=7.1 Hz,
3H), 4.18 (q, J=7.1 Hz, 2H), 5.24 (s, 2H), 7.00 (m, 8H), 7.37 (m,
10H), 7.61 (m, 1H), 7.88 (d, J=8.6 Hz, 1H), 8.61 (d, J=6.8 Hz,
1H).
27.3 Synthesis of
1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one 51
[0639] A mixture of intermediate a106 (0.43 g, 0.81 mmol) and 7 N
HCl (7 mL) is stirred under reflux for 13 h. The reaction mixture
is cooled to room temperature, and the formed precipitate is
separated by filtration and washed with 2 N HCl. The filtrate is
neutralized with solid K.sub.2CO.sub.3 and subjected to extraction
with the mixture tert-butanol/chloroform 1/1 (v/v) (3.times.30 mL).
The combined extracts are dried over anhydrous Na.sub.2SO.sub.4.
The solvents are removed under reduced pressure, and the residue is
purified by chromatography on silica gel (AcOEt/MeOH 1/1 v/v), then
by chromatography on basic aluminum oxide (gradient
chloroform/methanol from 40/0 to 40/1 v/v) to give
1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one 51
(0.034 g). Yield: 20%. LC-MS (MH.sup.+): 215.
Example 28
Synthesis of
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide
52
##STR00094##
[0640] 28.1 Synthesis of tert-butyl(5-chloro-2-methylphenyl)acetate
a108
[0641] A solution of P(t-Bu).sub.3 (0.0757 M, 5.19 mL, 0.393 mmol)
and a solution of 4-chloro-2-iodo-1-methylbenzene a107 (5.0 g, 19.8
mmol) and tert-butyl acetate (2.53 g, 21.8 mmol) in degassed
toluene (50 mL) are added to a mixture of LiHMDS (7.60 g, 45.5
mmol) and Pd(dba).sub.2 (0.226 g, 0.393 mmol), under argon
atmosphere. The reaction mixture is stirred at room temperature for
20 hours (according to the LC-MS data, 2-3 hours are sufficient for
the reaction to go to completion) and it is quenched with a
saturated ammonium chloride solution (50 mL). After 15 min the
organic layer is separated, and the aqueous layer is extracted with
diethylether. The combined organic extracts are dried over
anhydrous Na.sub.2SO.sub.4 and evaporated. The residue is purified
by chromatography on silicagel (petroleum ether/AcOEt 10/1 v/v) to
afford, after evaporation,
tert-butyl(5-chloro-2-methylphenyl)acetate a108 (3.70 g) as a
yellow oil (90% purity). Yield: 77%.
[0642] .sup.1H NMR .delta..sub.H (CDCl.sub.3, 400 MHz, ppm): 1.44
(s, 9H); 2.26 (s, 3H); 3.50 (s, 2H), 7.06-7.19 (m, 3H).
28.2 Synthesis of methyl(5-chloro-2-methylphenyl)acetate a109
[0643] HCl (2.3 M in methanol, 33.3 mL, 76.5 mmol) is added to
tert-butyl(5-chloro-2-methylphenyl)acetate a108 (3.70 g, 15.3
mmol), and the reaction mixture is stirred at 50-55.degree. C. for
20 hours. The reaction mixture is concentrated under reduced
pressure, the residue is dissolved in ethyl acetate, washed with a
saturated solution of NaHCO.sub.3, dried over anhydrous
Na.sub.2SO.sub.4, and the solution is concentrated to give 2.43 g
of methyl(5-chloro-2-methylphenyl)acetate a109 (85% purity). Yield:
80%.
[0644] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 2.27 (s, 3H),
3.60 (s, 2H), 3.70 (s, 3,H), 7.09-7.23 (m, 3H).
28.3 Synthesis of methyl[2-(bromomethyl)-5-chlorophenyl]acetate
a110
[0645] To a solution of methyl(5-chloro-2-methylphenyl)acetate a109
(2.40 g, 12.1 mmol) in dry benzene (5 mL), benzoyl peroxide (0.025
g, 0.1 mmol) is added and the mixture is heated to intense reflux.
A mixture of NBS (2.05 g, 11.5 mmol) and benzoyl peroxide (0.025 g,
0.1 mmol) is added portionwise over 20-25 minutes. The reaction
mixture is brought to reflux for another 40 min, and it is cooled
down to room temperature and diluted with an equal volume of
hexane. The precipitate is filtered off, washed with hexane, with
hexane/ether mixture (1/1 v/v) and once again with hexane. The
filtrates are combined and concentrated. To give a mixture of
methyl[2-(bromomethyl)-5-chlorophenyl]acetate a110 (3.37 g) with
starting compound in 66:17 ratio (according to GC-MS data), which
is used in the next step without further purification. GC-MS
(M.sup.+): 277.
[0646] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 3.72 (s, 3H),
3.77 (s, 2H), 4.53 (s, 2H), 7.25-7.32 (m, 3H).
28.4 Synthesis of methyl
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoate
a111
[0647] To a stirred suspension of methyl alaninate hydrochloride
(1.48 g, 10.6 mmol) in absolute acetonitrile (15 mL), iPr.sub.2NEt
(3.5 mL, 20.2 mmol) is added. After 5 min the precipitate is
dissolved, and a clear solution is formed, to which a solution of
crude methyl[2-(bromomethyl)-5-chlorophenyl]acetate a110 (1.65 g,
5.9 mmol) in absolute acetonitrile (5 mL) is added. The reaction
mixture is stirred at 75-80.degree. C. for 25 hours, and for
another 20 hours at room temperature. The solvents are removed
under reduced pressure, and the residue is dissolved with 100 mL of
methylene chloride. The solution is washed with a 10% solution of
NaHSO.sub.4 (2.times.25 mL), dried over anhydrous Na.sub.2SO.sub.4,
and the solvent is removed under reduced pressure. The residue
(1.87 g) is purified by chromatography silicagel (petroleum
ether/AcOEt 3/2 v/v) to afford methyl
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoate a111
(0.683 g). Yield: 43% (for 2 steps).
[0648] .sup.1H NMR .delta..sub.H (CDCl.sub.3, ppm): 1.47 (d, J=7.33
Hz, 3H), 3.62 (s, 2H), 3.71 (s, 3H); 4.43 (dd, J=29.84 Hz, J=15.40
Hz, 2H); 5.35 (q, J=7.33 Hz, 1H), 7.11-7.23 (m, 3H).
28.5 Synthesis of
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide
52
[0649] Methyl
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoate a111
(0.683 g, 2.55 mmol) is dissolved in 5 mL of saturated ammonia in
methanol and the reaction mixture is allowed to stand at room
temperature. After 5 days, another 5 mL of saturated methanolic
ammonia are added. After 2 more days the solvents are removed under
reduced pressure. The residue (0.618 g) is washed with hexane and
dried in vacuum to afford 0.552 g of
2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide
52.
[0650] Yield: 85%. LC-MS (MH.sup.+): 253/255.
Example 29
Synthesis of
5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one
53
##STR00095##
[0651] 29.1 Synthesis of tert-butyl(2-chloro-6-methylphenyl)acetate
a113
[0652] A 0.0757 M solution of P(t-Bu).sub.3 in toluene (5.19 mL,
0.393 mmol), a solution of 3-chloro-2-iodotoluene a112 (5.0 g, 19.8
mmol) in degassed toluene (10 mL) and a solution of
tert-butylacetate (2.53 g, 21.8 mmol) in degassed toluene (10 mL)
are sequentially added to a mixture of LiHMDS (7.60 g, 45.5 mmol)
and Pd(dba).sub.2 (0.226 g, 0.393 mmol) in degassed toluene (35 mL)
under stirring in argon. The reaction mixture is stirred at room
temperature for 2 h and decomposed by the addition of a saturated
NH.sub.4Cl solution (50 mL). After 15 min, the organic layer is
separated, and the aqueous layer is subjected to extraction with
diethylether. The combined organic extracts are dried over
anhydrous Na.sub.2SO.sub.4 and evaporated. The residue (6.38 g) is
purified by chromatography on silicagel (petroleum ether/AcOEt 10/1
v/v). The solvents are removed to afford
tert-butyl(2-chloro-6-methylphenyl)acetate a113 as a light-yellow
oil (4.80 g). Yield: 100%.
[0653] GC-MS (M.sup.+-(C.sub.4H.sub.8)): 184.
29.2 Synthesis of methyl(2-chloro-6-methylphenyl)acetate a114
[0654] 2.6 M HCl in methanol (30 mL, 78 mmol, 3.9 eq) is added to
tert-butyl(2-chloro-6-methyl-phenyl)acetate a113 (4.80 g, 19.8
mmol). The reaction mixture is stirred at 50-55.degree. C. for 4 h
and evaporated under reduced pressure. The residue is dissolved in
ethyl acetate. The solution is washed with a saturated NaHCO.sub.3
solution, dried over anhydrous Na.sub.2SO.sub.4, and evaporated to
give methyl(2-chloro-6-methylphenyl)acetate a114 as a light-yellow
oil (3.20 g). Yield: 81%.
[0655] .sup.1H NMR .delta..sub.H (DMSO, ppm): 2.29 (s, 3H), 3.63
(s, 3H), 3.86 (s, 2H), 7.18 (m, 2H), 7.29 (m, 1H).
29.3 Synthesis of methyl[2-(bromomethyl)-6-chlorophenyl]acetate
a115
[0656] Benzoyl peroxide (30 mg) is added to a solution of
methyl(2-chloro-6-methylphenyl)acetate a114 (3.20 g, 16.1 mmol) in
dry benzene 10 mL, and the mixture is refluxed intensively. The
mixture of NBS (2.72 g, 15.3 mmol) and benzoyl peroxide (35 mg) is
added in portions under stirring for 35 min. The reaction mixture
is refluxed additionally for 1 h, cooled to room temperature, and
diluted with hexane (20 mL). The formed precipitate is separated by
filtration, washed with hexane, a 1/1 hexane-ether mixture and
hexane again. The filtrates are combined and evaporated to give the
mixture (4.3 g, 96%) of
methyl[2-(bromomethyl)-6-chlorophenyl]acetate a115 with starting
compound a114 in the molar ratio 2:1 according to the .sup.1H NMR
data. The mixture is used as such in the next step. GC-MS
(M.sup.+): 278.
29.4 Synthesis of
5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one
53
[0657] To the previous mixture containing intermediate a115 (0.44
g, 1.15 mmol, 73 wt %) is added (1H-imidazol-4-ylmethyl)amine
dihydrochloride (0.59 g, 3.46 mmol, 3 eq) [from A. Turner et al.,
J. Am. Chem. Soc. (1949), 71, 2801-2803.], and anhydrous cesium
carbonate (1.88 g, 5.76 mmol, 5 eq) in dry DMF (15 mL). The mixture
is vigorously stirred at 60.degree. C. for 3 h. The reaction
mixture is cooled, concentrated under reduced pressure, diluted
with water, and subjected to extraction with ethyl acetate (three
times). The combined organic extracts are washed with brine, dried
over anhydrous Na.sub.2SO.sub.4, and evaporated. The residue (0.35
g) is purified by chromatography on silicagel (gradient
CHCl.sub.3/MeOH from 20/1 to 10/1 v/v) to afford
5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one
53 (0.15 g).
[0658] Yield: 50%. LC-MS (MH.sup.+): 262/264.
Example 30
Synthesis of
2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide 54
##STR00096##
[0659] 30.1 Synthesis of 3-chloro-N-(4-chlorophenyl)propanamide
a117
[0660] In a tree-necked flask fitted with a magnetic stirrer and a
reflux condenser, under nitrogen atmosphere, 4-chloroaniline a116
(25.52 g, 200 mmol) is dissolved in acetone (40 mL). A solution of
3-chloropropanoyl chloride (10 mL, 100 mmol) in acetone (20 mL) is
added and after 0.5 h the reaction mixture is heated to reflux for
1.5 h. The reaction mixture is cooled down to room temperature,
quenched with HCl (5 N, 100 mL), filtered and concentrated. The
crude reaction mixture is recrystallized from MeOH/H.sub.2O (200
mL, 1/1 v/v) to afford 3-chloro-N-(4-chlorophenyl)propanamide a117
(20.21 g). Yield: 46%. GC-MS (M.sup.+): 217/219.
30.2 Synthesis of 6-chloro-3,4-dihydro-2(1H)-quinolinone a118
[0661] In a tree-necked flask fitted with a mechanical stirrer,
under nitrogen atmosphere, 3-chloro-N-(4-chlorophenyl)propanamide
a117 (10.9 g, 50 mmol) is heated to 140.degree. C. At this
temperature, AlCl.sub.3 (13.34 g, 100 mmol) is carefully added and
the reaction mixture is stirred at 140.degree. C. for 24 h. The
reaction mixture is cooled down to 0.degree. C., HCl/H.sub.2O (100
mL, 10/90 w/w) is carefully added, H.sub.2O (200 mL) is added and
the reaction mixture is filtered.
[0662] The obtained off-white solid is washed with H.sub.2O and
with hexane. The crude residue is then dissolved in acetone/EtOH at
room temperature, cooled down to 0.degree. C., filtered on celite
and the filtrate is concentrated to afford
6-chloro-3,4-dihydro-2(1H)-quinolinone a118 (5 g). Yield: 55%.
GC-MS (M.sup.+): 181/183.
30.3 Synthesis of
2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide 54
[0663] In a tree-necked flask fitted with a magnetic stirrer, under
nitrogen atmosphere, at room temperature,
6-chloro-3,4-dihydro-2(1H)-quinolinone a118 (2.5 g, 13.7 mmol) is
dissolved in DMF (75 mL). NaH (60% dispersion in mineral oil; 0.606
g, 15.14 mmol) is added and the heterogenous reaction mixture is
stirred at room temperature for 0.5 h. 2-bromoacetamide (2.28 g,
16.52 mmol) is then added, the clear solution is stirred at room
temperature for 1 h, quenched with saturated NH.sub.4Cl and water
and extracted with ethyl acetate (3 times). The organic phases are
washed with H.sub.2O, brine, dried over MgSO.sub.4 and
concentrated. The crude reaction mixture is triturated in Et.sub.2O
and recrystallized from EtOH to afford
2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide 54 (0.620
g, 2.6 mmol).
[0664] Yield: 19%
[0665] GC-MS (M.sup.+): 238/240.
[0666] Compounds 55, 57 and 58 may be synthesized according to the
same method.
Example 31
Synthesis of
1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one 56
##STR00097##
[0667] 31.1 Synthesis of
1-[(1-trityl-1H-imidazol-4-yl)methyl]-3,4-dihydro-2(1H)-quinolinone
a119
[0668] In a 50 mL three necked flask fitted with a magnetic stirrer
and a reflux condenser, 3,4-dihydro-2(1H)-quinolinone a104 (1.25 g,
8.5 mmol) is dissolved in DMF (20 mL). NaH (60% dispersion in
mineral oil; 0.44 g, 11.05 mmol) is added and the mixture is heated
at 60.degree. C. After 1 h 4-(chloromethyl)-1-trityl-1H-imidazole B
(3.66 g, 10 mmol) is added and the reaction mixture is further
heated for 2 h. The reaction mixture is cooled down to room
temperature, quenched with a saturated solution of NH.sub.4Cl and
concentrated under reduced pressure. The crude reaction mixture is
purified by chromatography on silicagel (eluent: EtOAc/MeOH 96/4
v/v) to afford
1-[(1-trityl-1H-imidazol-4-yl)methyl]-3,4-dihydro-2(1H)-quinolinone
a119, which is used without further purification in the next step.
Yield: 100%.
[0669] LC-MS (MH.sup.+): 470.
31.2 Synthesis of
1-(1H-imidazol-4-ylmethyl)-3,4-dihydro-2(1H)-quinolinone
hydrochloride 56
[0670] In a 100 mL, three necked flask fitted with a magnetic
stirrer,
1-[(1-trityl-1H-imidazol-4-yl)methyl]-3,4-dihydro-2(1H)-quinolinone
a119 (8.5 mmol) is dissolved in 2 N HCl (50 mL) and heated at
100.degree. C. for 1 h. The mixture is cooled down to room
temperature, filtered and the filtrate is concentrated to dryness
by azeotropy with toluene. The obtained crude reaction mixture is
purified by chromatography on silicagel (eluent:
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 8/1.8/0.2 v/v/v), treated with a
solution of HCl (2.2 N in Et.sub.2O; 2.5 mL), filtered and
recrystallized from EtOH/Et.sub.2O to afford
1-(1H-imidazol-4-ylmethyl)-3,4-dihydro-2(1H)-quinolinone
hydrochloride 56 (0.89 g). Yield: 40%. LC-MS (MH.sup.+): 228
Example 32
Synthesis of
7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3--
one 60
##STR00098##
[0671] 32.1 Synthesis of tert-butyl
7-chloro-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate
a121
[0672] Boc.sub.2O (1.34 g, 6.2 mmol), Et.sub.3N (0.43 mL, 3.1
mmol), and DMAP (0.38 g, 3.1 mmol) are sequentially added under
stirring in argon to a solution of
7-chloro-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one a120 (0.60 g, 3.1
mmol) in dry dichloromethane (18 mL). The mixture is stirred at
40.degree. C. for 18 h and poured into a saturated solution of
CuSO.sub.4 (10 mL). The organic layer is separated, and the aqueous
layer is extracted with ethyl acetate. The combined organic phases
are dried over anhydrous Na.sub.2SO.sub.4, and the solvents are
removed under reduced pressure. The residue (0.96 g) is purified by
chromatography on silicagel (hexane/AcOEt 2/1 v/v) to afford
tert-butyl
7-chloro-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate
a121 (0.72 g). Yield: 75%.
[0673] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.41 (s, 9H), 3.01
(m, 2H), 3.13 (m, 2H), 4.91 (s, 2H), 7.21-7.23 (m, 2H), 7.26 (s,
1H).
[0674] Tert-butyl
7-chloro-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate
a122 may be synthesized according to the same method.
[0675] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.41 (s, 9H), 3.01
(m, 2H), 3.13 (m, 2H), 4.91 (s, 2H), 7.21-7.23 (m, 2H), 7.26 (s,
1H).
32.2 Synthesis of
3-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorophenyl)propanoic
acid a123
[0676] A 1 N LiOH solution (7.0 mL, 7.0 mmol) is added dropwise
under stirring to a solution of tert-butyl
7-chloro-3-oxo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate
a121 (0.69 g, 2.33 mmol) in THF (12 mL). In 2 h, THF is evaporated
under reduced pressure. The aqueous residue is acidified with 10%
AcOH to pH 6, and the reaction mixture is extracted with ether
(3.times.30 mL). The combined organic extracts are dried over
anhydrous Na.sub.2SO.sub.4, and the solvent is removed under
reduced pressure to give
3-(2-{[(tert-butoxycarbonyl)amino]-methyl}-5-chlorophenyl)propanoic
acid a123 (0.80 g). Yield: 100%.
[0677] .sup.1H NMR .delta..sub.H (DMSO, ppm): 1.38 (s, 9H), 2.48
(m, 2H+solvent peak), 2.83 (t, J=7.6 Hz, 2H), 4.13 (d, J=6.1 Hz,
2H), 7.22 (d, J=2.2 Hz, 3H), 7.34 (m, 1H).
[0678]
(2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-chlorophenyl)acetic acid
a124 may be synthesized according to the same method and is used as
such in the next step.
32.3 Synthesis of 3-[2-(aminomethyl)-5-chlorophenyl]propanoic acid
hydrochloride a125
[0679] 4 N HCl in dioxane (6.0 mL, 24 mmol) is added under stirring
to a solution of
3-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorophenyl)propanoic
acid a123 (0.78 g, 2.48 mmol) in absolute dioxane (10 mL). The
mixture is stirred at room temperature overnight. Dioxane is
removed under reduced pressure, and the residue is washed with
diethylether, filtered, and vacuum-dried to give
3-[2-(aminomethyl)-5-chlorophenyl]propanoic acid hydrochloride a125
(0.60 g). Yield: 97%.
[0680] .sup.1H NMR .delta..sub.H (DMSO, ppm): 2.57 (t, J=7.8 Hz,
2H), 2.88 (t, J=7.6 Hz, 2H), 3.57 (s, 4H), 4.05 (s, 2H), 7.35 (m,
2H), 7.48 (m, 1H).
[0681] [2-(2-aminoethyl)-4-chlorophenyl]acetic acid hydrochloride
a126 may be synthesized according to the same method.
[0682] .sup.1H NMR .delta..sub.H (DMSO, ppm): 2.90 (m, 2H), 2.98
(m, 2H), 3.68 (s, 2H), 7.27 (m, 2H), 7.33 (s, 1H), 8.10 (m,
3H).
32.4 Synthesis of
345-chloro-2-({[(1-trityl-1H-imidazol-4-yl)methyl]amino}methyl)phenyl]pro-
panoic acid a128
[0683] 3-[2-(aminomethyl)-5-chlorophenyl]propanoic acid
hydrochloride a125 (0.54 g, 2.16 mmol), Et.sub.3N (1.8 mL, 13.0
mmol), and trimethylorthoformate (0.30 mL, 2.16 mmol) are added
under stirring and prevention from entrance of air moisture to a
solution of 1-trityl-1H-imidazole-4-carbaldehyde (0.73 g, 2.16
mmol) in absolute methanol (76 mL), and the mixture is stirred at
room temperature for 16 h. NaBH.sub.4 (0.13 g, 3.45 mmol) is added,
and the mixture is stirred for 1 h and quenched by the addition of
a saturated NaHCO.sub.3 solution to pH 5-6. The solvents are
removed under reduced pressure, and the obtained mass is subjected
to extraction with ethyl acetate. Water is added to the residue,
and undissolved residue is separated by filtration and dried to
give
3-[5-chloro-2-({[(1-trityl-1H-imidazol-4-yl)methyl]amino}methyl)phenyl]pr-
opanoic acid a128 (0.71 g). The organic extract is dried over
anhydrous Na.sub.2SO.sub.4 and evaporated to give additionally
intermediate a128 (0.40 g).
[0684] The total yield of intermediate a128 is 1.11 g. Yield:
96%.
[0685] .sup.1H NMR .delta..sub.H (DMSO, ppm): 2.48 (m, 2H), 2.81
(t, J=7.6 Hz, 2H), 3.86 (s, 2H), 3.93 (s, 2H), 6.96 (s, 1H), 7.10
(m, 6H), 7.20-7.48 (m, 13H).
[0686]
[4-chloro-2-(2-{[(1-trityl-1H-imidazol-4-yl)methyl]amino}ethyl)phen-
yl]acetic acid a129 may be synthesized according to the same
method.
[0687] .sup.1H NMR .delta..sub.H (DMSO, ppm): (m, 2H), 3.06 (m,
2H), 3.65 (s, 2H), 4.07 (s, 2H), 7.10 (m, 7H), 7.28 (m, 3H), 7.41
(m, 9H), 7.51 (s, 1H).
32.5 Synthesis of
7-chloro-2-[(1-trityl-1H-imidazol-4-yl)methyl]-1,2,4,5-tetrahydro-3H-2-be-
nzazepin-3-one a130
[0688] DIEA (2.2 mL, 12.42 mmol) is added under stirring in argon
to a solution of
345-chloro-2-({[(1-trityl-1H-imidazol-4-yl)methyl]amino}methyl)phenyl]pro-
panoic acid a128 (1.11 g, 2.07 mmol) in dry dichloroethane (290
mL). The mixture is stirred for 20 min,
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU, 0.73 g, 2.28 mmol) is added, and the
mixture is stirred at room temperature overnight. A saturated
NaHCO.sub.3 solution is added, and the organic layer is separated.
The aqueous layer is subjected to extraction with dichloromethane,
and the combined organic extracts are dried over anhydrous
Na.sub.2SO.sub.4. The organic solvents are removed under reduced
pressure, and the residue (1.65 g) is purified by chromatography on
silicagel (chloroform/methanol 50:1) to give intermediate a130
(0.92 g). Yield: 85.5%.
[0689] .sup.1H NMR .delta..sub.H (DMSO, ppm): 2.80 (m, 2H), 2.95
(m, 2H), 4.42 (s, 2H), 4.56 (s, 2H), 5.75 (m, 2H), 6.43 (s, 1H),
6.94 (m, 8H), 7.16 (d, J=1.90 Hz, 1H), 7.20 (d, J=1.23 Hz, 1H),
7.37 (m, 9H).
[0690]
7-chloro-3-[(1-trityl-1H-imidazol-4-yl)methyl]-1,3,4,5-tetrahydro-2-
H-3-benzazepin-2-one a131 may be synthesized according to the same
method.
[0691] .sup.1H NMR .delta..sub.H (DMSO, ppm): 2.84 (t, J=5.4 Hz,
2H), 3.76 (m, 2H), 3.83 (s, 2H), 4.40 (s, 2H), 6.70 (d, J=1.0 Hz,
1H), 7.05 (m, 7H), 7.15 (s, 2H), 7.32 (d, J=1.2 Hz, 1H), 7.37 (m,
9H)
32.6 Synthesis of
7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3--
one hydrochloride 60
[0692] 4 N HCl in dioxane (18.0 mL, 72 mmol) is added under
stirring and prevention from entrance of air moisture to a solution
of intermediate a130 (0.68 g, 1.30 mmol) in absolute dioxane (8.5
mL), and the mixture is stirred at room temperature for 52 h. The
formed precipitate is separated by filtration, washed three times
with diethylether, and vacuum-dried to give
7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazep-
in-3-one hydrochloride 60 as a white powder (0.247 g). Yield:
61%.
[0693] .sup.1H NMR .delta..sub.H (DMSO, ppm): 2.87 (m, 2H), 3.08
(m, 2H), 4.64 (d, J=16.31 Hz, 4H), 7.15 (s, 2H), 7.24 (s, 1H), 7.46
(s, 1H), 8.97 (d, J=1.00 Hz, 1H), 14.48 (s, 1H).
[0694] Compound 61 may be prepared according to the same
method.
Example 33
Synthesis of
7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,-
5-tetrahydro-3H-2-benzazepin-3-one 59
##STR00099##
[0695] 33.1 Synthesis of
3-(chloromethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine a132
[0696] 3-(chloromethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
a132 is prepared immediately prior to the synthesis from its
hydrochloride (0.15 g, 0.55 mmol) [synthesized according to the
methods described by S. Mavel et al in Bioorg. Med. Chem. (2002),
10, 941-946 or by J. J. Kaminski, A. M. Doweyko in J. Med. Chem.
(1997), 40, 427-436].
[0697] A suspension of
3-(chloromethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
hydrochloride (0.15 g, 0.55 mmol) in dry diethylether (5 mL) is
treated with iPrEt.sub.2N (0.10 mL, 0.58 mmol) under stirring for 5
min, filtered, and evaporated. The residue is vacuum-dried for 1 h
to give 3-(chloromethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
a132 (0.127 g). Yield: 98%.
33.2 Synthesis of
7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,-
5-tetrahydro-3H-2-benzazepin-3-one 59
[0698] n-BuLi (1.6 M in hexane; 0.35 mL, 0.56 mmol) is added under
stirring in argon at -78.degree. C. to a solution of
7-chloro-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one a120 (0.108 g,
0.55 mmol) in absolute THF (15 mL). The mixture is stirred for 0.5
h, and a solution of
3-(chloromethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine a132
(0.130 g, 0.55 mmol) in absolute THF (5 mL) is added dropwise. The
reaction mixture is stirred at -70 to -50.degree. C. for 1 h, at
room temperature for 1 h, and at 60.degree. C. for 16 h. The
mixture is cooled to room temperature, and a saturated NH.sub.4Cl
solution (10 mL) is added. The organic layer is separated, and the
aqueous layer is extracted with dichloromethane. The combined
organic extracts are dried over anhydrous Na.sub.2SO.sub.4, and the
solvents are removed under reduced pressure. The residue is washed
5 times with dry diethylether and vacuum-dried to give
7-chloro-2-{[2-(trifluoromethyl)imidazo-[1,2-a]pyridin-3-yl]methyl}-1,2,4-
,5-tetrahydro-3H-2-benzazepin-3-one 59 (0.120 g).
[0699] Yield: 55%. LC-MS (MH.sup.+): 394.
[0700] Compound 62 may be prepared according to the same
method.
Example 34
Synthesis of
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanamide 68
##STR00100##
[0701] 34.1 Synthesis of 5-methoxy-3-propyl-3,4-dihydro-2H-pyrrole
a134
[0702] A solution of trimethyloxonium borofluoride (11.2 g, 76
mmol) in dry CH.sub.2Cl.sub.2 (60 mL) is added to a solution of
4-propylpyrrolidin-2-one a133 (8.0 g, 63 mmol) in dry
CH.sub.2Cl.sub.2 (60 mL). The reaction mixture is stirred at room
temperature for 16 h, diluted with CH.sub.2Cl.sub.2 (150 mL),
washed with 5% NaHCO.sub.3 and water, dried with anhydrous
Na.sub.2SO.sub.4, and evaporated in vacuum. The residue is
dissolved in dry chloroform, passed through a layer of silica gel,
and eluted thrice with chloroform. The combined filtrates are
evaporated in vacuum to afford
5-methoxy-3-propyl-3,4-dihydro-2H-pyrrole a134 (7.27 g). Yield:
82%.
[0703] .sup.1H NMR .delta..sub.H (DMSO, ppm): 0.87 (t, J=6.8 Hz,
3H), 1.20-1.38 (m, 4H), 2.08 (dd, J=6.87 and 16.1 Hz, 1H),
2.30-2.40 (m, 1H), 2.50-5.57 (m, 1H overlap with solvent), 3.11
(dt, J=5.87 and 13.7 Hz, 1H), 3.64 (dd, J=7.8 and 13.7 Hz, 1H),
3.67 (s, 3H).
34.2 Synthesis of [4-propylpyrrolidin-2-ylidene]cyanamide a135
[0704] 5-methoxy-3-propyl-3,4-dihydro-2H-pyrrole a134 (4.0 g, 28
mmol) is dissolved in methanol (60 mL). A 50% solution of cyanamide
(2.62 g, 2.43 mL, 31 mmol) in water is added and the reaction
mixture is stirred at room temperature for 2 h. The solvents are
evaporated in vacuum. The residue is dried in a vacuum desiccator
over anhydrous CaCl2 to afford 4.28 g of
[4-propylpyrrolidin-2-ylidene]cyanamide a135. Yield: 99%.
[0705] LC-MS (MH.sup.+): 152.
34.3 Synthesis of ethyl
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanoate a136
[0706] A 60% suspension of NaH in mineral oil (67 mg, 1.67 mmol) is
added in portions to a stirred solution of
[4-propylpyrrolidin-2-ylidene]cyanamide a135 (230 mg, 1.52 mmol) in
absolute DMF (4 mL), under argon. The reaction mixture is stirred
at room temperature for 30 min., then ethyl 2-bromobutanoate (311
mg, 236 .mu.L, 1.60 mmol) is added dropwise. The reaction mixture
is stirred for 3 h, then decomposed with brine. The resulting
mixture is extracted three times with ethyl acetate. The combined
organic layers are washed with brine and dried over anhydrous
Na.sub.2SO.sub.4. The solvents are removed under reduced pressure.
The residue (490 mg) is purified by chromatography on silicagel
(eluent: hexane/ethyl acetate 2:1) to afford 0.30 g of ethyl
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanoate a136.
Yield: 74%.
[0707] LC-MS (MH.sup.+): 266.
[0708]
[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]cyana-
mide 65 may be synthesized according to the same method.
34.4 Synthesis of
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanamide 68
[0709] Ethyl
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanoate a136 (250
mg, 0.94 mmol) is dissolved in a 7 M methanol solution of ammonia
(30 mL). The reaction mixture is stirred at room temperature for 10
h, and evaporated to dryness under reduced pressure. The residue is
triturated with a 1:1 ether/pentane mixture, filtered off, and
dried to afford 190 mg of
2-[(2E)-2-(cyanoimino)-4-propylpyrrolidin-1-yl]butanamide 68.
Yield: 86%. LC-MS (MH.sup.+): 237.
[0710] Compounds 66 and 67 may be synthesized according to the same
method.
Example 35
Synthesis of
N-[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]methanesu-
lfonamide 69
##STR00101##
[0711] 35.1 Synthesis of
N-[(2E)-4-propylpyrrolidin-2-ylidene]methanesulfonamide a137
[0712] A mixture of 5-methoxy-3-propyl-3,4-dihydro-2H-pyrrole a134
(300 mg, 2.13 mmol) and methanesulfonamide (134 mg, 1.42 mmol) in
absolute methanol (5 mL) is refluxed for 3 days under anhydrous
conditions. The reaction mixture is cooled to room temperature and
evaporated to dryness under reduced pressure. The residue is
purified by chromatography on silicagel (eluent: hexane/ethyl
acetate 1:1) to afford 240 mg of crude
N-[(2E)-4-propylpyrrolidin-2-ylidene]methanesulfonamide a137 as a
colorless powder which is used for the next step without any
further purification. Yield: 83%.
[0713] LC-MS (MH.sup.+): 205.
35.2 Synthesis of
N-[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]methanesu-
lfonamide 69
[0714]
N-[(2E)-1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-ylidene]met-
hanesulfonamide 69 may be synthesised from
N-[(2E)-4-propylpyrrolidin-2-ylidene]methanesulfonamide a137,
according to the method described in example 34.3.
[0715] LC-MS (MH.sup.+): 285.
[0716] Table I indicates the IUPAC name of the compound, the ion
peak observed in mass spectroscopy and the .sup.1H NMR
description.
TABLE-US-00007 TABLE I Physical Characterization of Example
Compounds. MH.sup.+ .sup.1H NMR .delta..sub.H (400 MHZ, DMSO unless
n.sup.o IUPAC Name (M.sup.+.) otherwise specified) 1
(2S)-2-[3-(4-nitrophenyl)-5- (292) (250 MHz): 0.90 (t, J = 8.1 Hz,
3 H), oxoimidazolidin-1-yl]butanamide 1.65-2.0 (m, 2 H), 4.1 (s, 2
H), 4.5 (m, 1 H), 4.90 (d, J = 2.9 Hz, 1 H), 5.05 (d, J = 2.9 Hz, 1
H), 6.75 (d, J = 7.4 Hz, 2 H), 7.10 (s, 1 H), 7.55 (s, 1 H), 8.15
(d, J = 7.4 Hz, 2 H) 2 (2S)-2-[3-(2,4-dinitrophenyl)-5- 338 (250
MHz): 0.85 (t, J = 7.5 Hz, 3 H), oxoimidazolidin-1-yl]butanamide
1.65-2.0 (m, 2 H), 4.0 (s, 2 H), 4.5 (m, 1 H), 4.9 (d, J = 3.7 Hz,
1 H), 5.10 (d, J = 43.7 Hz, 1 H), 7.15 (s, 1 H), 7.25 (d, J = 8.2
Hz, 1 H), 7.65 (s, 1 H), 8.3 (m, 1 H), 8.15 (s, 1 H) 3
(2S)-2-(5-oxo-3-phenylimidazolidin- (247) (250 MHz): 0.85 (t, J =
7.4 Hz, 3 H), 1-yl)butanamide 1.6-2.0 (m, 2 H), 3.9 (s, 2 H), 4.5
(m, 1 H), 4.75 (d, J = 2.9 Hz, 1 H), 4.90 (d, J = 2.9 Hz, 1 H),
6.65 (d, J = 8.0 Hz, 2 H), 6.75 (t, J = 8.0 Hz, 1 H), 7.1 (s, 1 H),
7.25 (t, J = 8.0 Hz, 2 H), 7.6 (s, 1 H) 4
2-[5-(iodomethyl)-2-oxo-1,3- 313 (250 MHz): 0.9 (t, J = 8.0 Hz, 3
H), 1.6 (m, 1 oxazolidin-3-yl]butanamide H), 1.85 (m, 1 H), 3.13
(m, 1 H), 3.50 (m, 2 H), 3.85 (t, J = 6.4 Hz, 1 H), 4.05 (m, 1 H),
4.57 (m, 1 H), 7.03 (s, 1 H), 7.50 (s, 1 H) 5
2-(2-oxo-2,5-dihydro-1H-pyrrol-1- (168) 0.80 (t, 3 H, 6.2 Hz),
1.5-2.0 (m, 2 H), 4.0 (d, yl)butanamide J = 20.8 Hz, 1 H), 4.3 (d,
J = 20.8 Hz, 1 H), 4.45 (m, 1 H), 6.1 (m, 1 H), 6.95 (s, 1 H), 7.3
(m, 1 H), 7.45 (s, 1 H) 6 2-(2-oxo-4-phenyl-2,5-dihydro-1H- 245
(250 MHz): 0.85 (t, J = 7.8 Hz, 3 H), pyrrol-1-yl)butanamide
1.7-2.2 (m, 2 H), 4.40-4.75 (m, 3 H), 6.6 (s, 1 H), 7.0 (s, 1 H),
7.40 (m, 4H), 7.7 (m, 2 H) 7 2-(4-methyl-2-oxo-2,5-dihydro-1H- 191
(250 MHz): 0.85 (t, J = 5.9 Hz, 3 H), pyrrol-1-yl)butanamide
1.5-1.95 (m, 2 H), 2.1 (s, 3 H), 3.9 (d, J = 18.4 Hz, 1 H), 4.2 (d,
J = 18.4 Hz, 1 H), 4.4 (m, 1 H), 5.8 (s, 1 H) 6.95 (s, 1 H), 7.4
(s, 1 H) 8 (+)-(2S)-2-(2-oxo-4-propyl-2,5- 211 (250 MHz): 0.95 (m,
6H), 1.5-2.1 (m, 4H), dihydro-1H-pyrrol-1-yl)butanamide 2.35 (m, 2
H), 3.85 (d, J = 25.1 Hz, 1 H), 4.05 (d, J = 25.1 Hz, 1 H), 4.50
(m, 1 H), 5.5 (s, 1 H), 5.85 (s, 1 H), 6.4 (s, 1 H) 9
(2S)-2-(2-oxo-5-propyl-1,3-thiazol- 229 0.78 (t, J = 7.3 Hz, 3 H),
0.89 (t, 3 H, J = 7.3 Hz), 3(2H)-yl)butanamide 1.47-1.52 (m, 2 H),
1.76-1.94 (m, 2 H), 2.46 (t, J = 7.3 Hz, 2 H), 4.6 (dd, J = 10.1
Hz, J = 5.6 Hz, 1 H), 6.82 (s, 1 H), 7.23 (s, 1 H), 7.67 (s, 1 H)
10 2-(2-oxo-5-propyl-1,3-thiazol- 215 0.90 (t, J = 7.3 Hz, 3 H),
1.43-1.52 (m, 5H), 3(2H)-yl)propanamide 2.45 (m, 2 H), 4.74 (q, J =
7.3 Hz, 1 H), 6.81 (s, 1 H), 7.19 (s, 1 H), 7.59 (s, 1 H) 11
2-(5-butyl-2-oxo-1,3-thiazolidin-3- 245 (CDCl.sub.3): 0.85-1.1 (m,
6 H), 1.35 (m, 4 H), yl)butanamide 1.58-1.93 (m, 3 H), 1.97 (m, 1
H), 3.26-3.36 (m, 1 H), 3.64-3.79 (m, 2 H), 4.48 (m, 1 H), 5.41 (s,
1 H), 6.05 (s, 1 H) 12 2-(5-butyl-2-oxo-1,3-thiazolidin-3- 231
(CDCl.sub.3): 0.92 (m, 3 H), 1.29-1.43 (m, 6 H), yl)propanamide
1.64 (s, 1 H), 1.74 (m, 2 H), 3.31 (m, 1 H), 3.72 (m, 2 H), 4.75
(m, 1 H), 5.42 (s, 1 H), 6.05 (s, 1 H) 13
2-(2-oxo-5-phenyl-1,3-thiazolidin-3- 251 1.34 (dd, J = 14.1, 7.3
Hz, 3 H), 3.79 (m, 1 yl)propanamide H), 4.09 (m, 1 H), 4.57 (m, 1
H), 5.09 (dt, J = 18.2, 7.3 Hz, 1 H), 7.13 (d, J = 17.4 Hz, 1 H),
7.29-7.44 (m, 3 H), 7.45-7.58 (m, 3 H) 14
2-(2-oxo-5-propyl-1,3-thiazolidin-3- 231 0.84 (t, J = 7.3 Hz, 3 H),
0.90 (t, J = 7.1 Hz, yl)butanamide 3 H), 1.35 (m, 2 H), 1.63 (m, 2
H), 1.73 (m, 1 H), 1.83 (m, 1 H), 3.26 (dd, J = 10.4, 6.3 Hz, 1 H),
3.81 (m, 1 H), 3.94 (dd, J = 10.1 Hz, J = 7.1 Hz, 1 H), 4.33 (dd, J
= 10.4, 5.3 Hz, 1 H), 7.11 (s, 1 H), 7.50 (s, 1 H) 15
2-(2-oxo-5-phenyl-1,3-thiazolidin-3- 265 0.79 (t, J = 7.1 Hz, 3 H),
0.89 (t, J = 7.1 Hz, yl)butanamide 3 H), 1.5-1.85 (m, 4H), 3.54 (m,
1 H), 3.97 (m, 2 H), 4.22 (m, 1 H), 4.41 (m, 2 H), 5.06 (m, 2 H),
7.14 (m, 2 H), 7.30-7.61 (m, 12 H) 16
2-(2-oxo-5-propyl-1,3-thiazolidin-3- 217 0.91 (t, J = 7.3 Hz, 3 H),
1.29 (d, J = 7.3 Hz, yl)propanamide 3 H), 1.36 (dd, J = 14.9, J =
7.3 Hz, 2 H), 1.52-1.88 (m, 2 H), 3.32-3.50 (m, 1 H), 3.66-3.96 (m,
2 H), 4.48 (m, 1 H), 7.09 (s, 1 H), 7.43 (s, 1 H) 17
(2S)-2-[2-oxo-5-(2,2,2- 271 0.84 (t, J = 7.3 Hz, 3 H), 1.59-2.88
(m, 2 H), trifluoroethyl)-1,3-thiazolidin-3- 2.77-2.99 (m, 2 H),
3.37 (dd, J = 10.4, J = 7.3 Hz, yl]butanamide 2 H), 3.61-3.79 (m, 1
H), 4.34 (m, 1 H), 7.13 (s, 1 H), 7.55 (s, 1 H) 18 1-{[6-chloro-2-
333/ (CDCl.sub.3): 1.78 (s, 4 H), 2.42 (s, 2 H), 3.27 (s,
(trifluoromethyl)imidazo[1,2- 335 2 H), 5.12 (s, 2 H), 7.19 (d, J =
9.5 Hz, 1 b]pyridazin-3-yl]methyl}piperidin-2- H), 7.97 (d, J = 9.5
Hz, 1 H) one 19 1-(1H-imidazol-4-ylmethyl)-5- 222 0.86 (t, J = 6.8
Hz, 3 H), 1.18-1.44 (m, 5 H), propylpiperidin-2-one hydrochloride
1.79 (m, 2 H), 2.29 (m, 2 H), 2.94 (m, 1 H), 3.44 (m, 1 H), 4.52
(m, 2 H), 7.55 (s, 1 H), 9.01 (s, 1 H), 14.42 (s, 1 H) 20
1-(1H-imidazol-1-ylmethyl)-5- 222 0.85 (t, J = 7.0 Hz, 3 H),
1.16-1.38 (m, 5 H), propylpiperidin-2-one 1.74 (m, 2 H), 2.30 (m, 2
H), 2.89 (m, 1 H), 3.39 (ddd, J = 11.5, 4.8, 1.5 Hz, 1 H), 5.34 (d,
J = 13.6 Hz, 1 H), 5.52 (d, J = 13.6 Hz, 1 H), 6.90 (s, 1 H), 7.17
(s, 1 H), 7.71 (s, 1 H) 21 1-(imidazo[1,2-a]pyridin-3- 272 0.83 (t,
J = 7.0 Hz, 3 H), 1.13-1.42 (m, 5 H),
ylmethyl)-5-propylpiperidin-2-one 1.77 (m, 2 H), 2.33 (m, 2 H),
2.90 (m, 1 H), trifluoroacetate 3.33 (m, 1 H), 4.96 (s, 2 H), 7.57
(td, J = 6.5, 1.5 Hz, 1 H), 7.98 (m, 2 H), 8.25 (s, 1 H), 8.89 (d,
J = 7.0 Hz, 1 H) 22 1-(1H-imidazol-1-ylmethyl)-5- 256 1.90 (m, 1
H), 2.01 (m, 1 H), 2.42 (dd, J = 6.3, phenylpiperidin-2-one 3.8 Hz,
1 H), 3.09 (m, 1 H), 3.32 (m, 2 H), 3.55 (ddd, J = 11.5, 5.0, 1.5
Hz, 1 H), 5.39 (m, 1 H), 5.56 (m, 1 H), 6.90 (s, 1 H), 7.20 (s, 1
H), 7.29 (m, 5 H), 7.71 (s, 1 H) 23 1-(imidazo[1,2-a]pyridin-3- 306
1.88 (m, 1 H), 1.95-2.05 (m, 1 H),
ylmethyl)-5-phenylpiperidin-2-one 2.40-2.48 (m, 2 H), 3.03 (m, 1
H), 3.22 (m, 1 H), 3.40 (m, 1 H), 4.91 (q, J = 15.3 Hz, 2 H), 6.96
(t, J = 6.8 Hz, 1 H), 7.23 (m, 6 H), 7.58 (m, 2 H), 8.56 (d, J =
6.8 Hz, 1 H) 24 1-(imidazo[1,2-a]pyridin-3- 306 1.95 (m, 2 H), 2.56
(d, J = 4.3 Hz, 2 H), ylmethyl)-4-phenylpiperidin-2-one 3.10 (m, 1
H), 3.37 (m, 2 H), 5.03 (dd, J = 52.5 Hz, hydrochloride J = 15.8
Hz, 2 H), 7.22 (m, 3 H), 7.29 (m, 2 H), 7.61 (td, J = 6.8, 1.5 Hz,
1 H), 8.01 (m, 2 H), 8.30 (s, 1 H), 8.94 (d, J = 7.0 Hz, 1 H) 25
1-(1H-imidazol-1-ylmethyl)-4- 256 2.62 (m, 2 H), 3.20 (m, 1 H),
3.71-3.81 (m, 1 phenylpiperidin-2-one H), 4.01 (m, 1 H), 4.16 (dd,
J = 7.5, 4.3 Hz, hydrochloride 2 H), 6.35 (m, 2 H), 7.86 (m, 3 H),
7.95 (m, 2 H), 8.36 (d, J = 13.3 Hz, 2 H), 9.86 (s, 1 H) 26
1-(imidazo[1,2-a]pyridin-3- 272 (CDCl.sub.3): 0.89 (t, J = 6.5 Hz,
3 H), ylmethyl)-4-propylpiperidin-2-one 1.23-1.45 (m, 5 H), 1.81
(m, 1 H), 1.93 (m, 1 H), hydrochloride 2.03 (dd, J = 17.6, 10.8 Hz,
1 H), 2.58 (ddd, J = 17.6, 4.8, 1.5 Hz, 1 H), 3.24-3.33 (m, 1 H),
3.35-3.42 (m, 1 H), 4.90 (d, J = 15.8 Hz, 1 H), 5.19 (d, J = 15.8
Hz, 1 H), 7.35 (t, J = 7.0 Hz, 1 H), 7.82 (m, 1 H), 8.13 (s, 1 H),
8.29 (d, J = 9.0 Hz, 1 H), 9.09 (d, J = 7.0 Hz, 1 H) 27
1-(1H-imidazol-5-ylmethyl)-4- 222 0.87 (t, J = 7.0 Hz, 3 H),
1.19-1.26 (m, 2 H), propylpiperidin-2-one 1.27-1.33 (m, 2 H),
1.36-1.45 (m, 1 H), trifluoroacetate 1.71-1.97 (m, 3 H), 2.36 (ddd,
J = 16.8, 4.5, 1.5 Hz, 1 H), 3.27 (m, 2 H), 4.53 (s, 2 H), 7.55 (s,
1 H), 8.99 (s, 1 H), 14.39 (m, 1 H) 28
1-(1H-imidazol-1-ylmethyl)-4- 222 0.84 (t, J = 7.0 Hz, 3 H),
1.14-1.41 (m, 5 H), propylpiperidin-2-one 1.71 (m, 1 H), 1.83 (m, 1
H), 1.94 (dd, J = 17.3, 10.8 Hz, 1 H), 2.37 (ddd, J = 17.3, 5.0,
2.0 Hz, 1 H), 3.23 (ddd, J = 11 Hz, J = 11 Hz, J = 4.8 Hz, 1 H),
3.36 (ddd, J = 12.0, 5.5, 3.5 Hz, 1 H), 5.39 (d, J = 13.6 Hz, 1 H),
5.49 (d, J = 13.6 Hz, 1 H), 6.91 (s, 1 H), 7.17 (s, 1 H), 7.71 (s,
1 H) 29 1-{[6-chloro-2- 347/ (CDCl.sub.3): 1.39 (m, 2 H), 1.67 (m,
4 H), (trifluoromethyl)imidazo[1,2- 349 2.57 (m, 2 H), 3.38 (m, 2
H), 5.12 (s, 2 H), b]pyridazin-3-yl]methyl}azepan-2- 7.20 (d, J =
9.5 Hz, 1 H), 7.98 (d, J = 9.5 Hz, 1 one H) 30
1-(1H-imidazol-5-ylmethyl)-5- 236 0.83 (t, J = 7.0 Hz, 3 H), 0.92
(m, 1 H), propylazepan-2-one 1.04 (m, 1 H), 1.13 (m, 2 H), 1.25 (m,
2 H), 1.46 (m, 1 H), 1.70 (m, 2 H), 2.31 (dd, J = 13.6, 7.5 Hz, 1
H), 2.54 (m, 1 H), 3.37 (m, 2 H), 4.31 (m, 1 H), 4.42 (m, 1 H),
6.88 (s, 1 H), 7.53 (s, 1 H), 11.87 (m, 1 H) 31 5-propyl-1-{[2- 354
0.44 (m, 1 H), 0.77 (t, J = 7.0 Hz, 3 H),
(trifluoromethyl)imidazo[1,2- 0.99 (m, 3 H), 1.14 (m, 2 H), 1.48
(m, 2 H), a]pyridin-3-yl]methyl}azepan-2-one 1.75 (m, 1 H), 2.42
(dd, J = 13.6, 7.5 Hz, 1 H), 2.64 (t, J = 13.1 Hz, 1 H), 3.09 (dd,
J = 15.3, 6.3 Hz, 1 H), 3.42 (dd, J = 15.3, 10.5 Hz, 1 H), 5.01
(dd, J = 57 Hz, J = 15.8 Hz, 2 H), 7.17 (td, J = 6.8, 0.8 Hz, 1 H),
7.49 (ddd, J = 8.8 Hz, J = 6.5 Hz, J = 0.8 Hz, 1 H), 7.73 (d, J =
9.3 Hz, 1 H), 8.44 (d, J = 7.0 Hz, 1 H)
1-(1H-imidazol-5-ylmethyl)-5- 270 1.44 (m, 1 H), 1.58 (q, J = 12.8
Hz, 1 H), phenylazepan-2-one 1.80 (m, 2 H), 2.40 (dd, J = 13.6, 7.0
Hz, 1 H), 2.75 (t, J = 12.5 Hz, 2 H), 3.40 (dd, J = 15.3, 5.5 Hz, 1
H), 3.55 (dd, J = 15.3, 10.5 Hz, 1 H), 4.37 (d, J = 14.8 Hz, 1 H),
4.51 (d, J = 14.8 Hz, 1 H), 6.94 (s, 1 H), 7.17 (m, 3 H), 7.27 (m,
2 H), 7.56 (s, 1 H) 32 5-phenyl-1-{[2- 388 0.90 (q, J = 12.0 Hz, 1
H), 1.49 (q, J = 12.5 Hz, (trifluoromethyl)imidazo[1,2- 1 H),
1.59-1.68 (m, 1 H), 1.81-1.91 (m, 1
a]pyridin-3-yl]methyl}azepan-2-one H), 2.49 (m, 1 H), 2.73 (m, 1
H), 2.85 (t, J = 12.8 Hz, 1 H), 3.13 (dd, J = 15.3, 5.8 Hz, 1 H),
3.61 (dd, J = 15.3, 10.8 Hz, 1 H), 5.02 (d, J = 15.8 Hz, 1 H), 5.17
(d, J = 15.8 Hz, 1 H), 6.96 (d, J = 7.3 Hz, 2 H), 7.14 (m, 1 H),
7.22 (m, 3 H), 7.53 (m, 1 H), 7.75 (d, J = 9.3 Hz, 1 H), 8.49 (d, J
= 7.0 Hz, 1 H) 33 1-(1H-imidazol-5-ylmethyl)-6- 236 0.85 (t, J =
7.0 Hz, 3 H), 1.19 (m, 3 H), propylazepan-2-one 1.29 (m, 3 H),
1.44-1.75 (m, 3 H), 2.32 (m, 1 H), 2.43 (dd, J = 13.6, 9.8 Hz, 1
H), 4.37 (dd, J = 33.1 Hz, J = 14.6 Hz, 2 H), 6.91 (s, 1 H), 7.58
(s, 1 H) 34 1-(1H-imidazol-4-ylmethyl)-4- 236 0.78 (t, J = 7.3 Hz,
3 H), 0.96-1.10 (m, 2 H), propylazepan-2-one 1.10-1.28 (m, 4 H),
1.39 (m, 1 H), 1.65-1.80 (m, 2 H), 2.24-2.37 (m, 1 H), 2.46-2.62
(m, 1 H), 3.10-3.26 (m, 2 H), 4.26 (d, J = 14.8 Hz, 1 H), 4.49 (d,
J = 14.6 Hz, 1 H), 6.92 (s, 1 H), 7.57 (s, 1 H) 35
4-(1H-imidazol-4-ylmethyl)-4,6- 220 3.61 (s, 2 H), 4.69 (s, 2 H),
6.88 (d, J = 5.0 Hz, dihydro-5H-thieno[3,2-b]pyrrol-5- 1 H), 7.03
(s, 1 H), 7.40 (d, J = 5.0 Hz, 1 one H), 7.54 (s, 1 H), 11.95 (m, 1
H) 36 2-(5-oxo-5,6-dihydro-4H- 197 (CDCl3): 3.68 (s, 2 H), 4.35 (s,
2 H), 5.38 (s, thieno[3,2-b]pyrrol-4-yl)acetamide 1 H), 5.93 (s, 1
H), 6.81 (d, J = 5.3 Hz, 1 H) and 7.2 (d, J = 5.0 Hz, 1 H) 37
4-{[2-(trifluoromethyl)imidazo[1,2- 338 3.73 (s, 2 H), 5.36 (s, 2
H), 6.58 (d, J = 5.0 Hz, a]pyridin-3-yl]methyl}-4,6-dihydro- 1 H),
7.17 (t, J = 6.8 Hz, 1 H), 7.49 (m, 2
5H-thieno[3,2-b]pyrrol-5-one H), 7.73 (d, J = 9.0 Hz, 1 H), 8.50
(d, J = 7.0 Hz, 1 H) 38 4-{[2-(trifluoromethyl)imidazo[1,2- 342
1.74-1.88 (m, 1 H), 2.23 (m, 1 H), 2.39 (dd,
a]pyridin-3-yl]methyl}hexahydro- J = 17.6, 2.0 Hz, 1 H), 2.55 (m, 1
H), 5H-thieno[3,2-b]pyrrol-5-one 2.69-2.77 (m, 1 H), 2.86 (m, 1 H),
3.88 (m, 1 H), 4.09 (m, 1 H), 4.76 (d, J = 16.3 Hz, 1 H), 5.14 (d,
J = 16.3 Hz, 1 H), 7.16 (td, J = 6.8, 0.8 Hz, 1 H), 7.49 (m, 1 H),
7.72 (d, J = 9.3 Hz, 1 H), 8.51 (d, J = 7.0 Hz, 1 H) 39
1-(1H-imidazol-4-ylmethyl)-1H- 220 3.43 (s, 2 H), 4.66 (s, 2 H),
6.50 (d, J = 2.3 Hz, thieno[3,4-b]pyrrol-2(3H)-one 1 H), 7.14 (d, J
= 44.7 Hz, 2 H), 7.57 (m, 1 H) 40 2-(6-bromo-2-oxo-1,3- 287/ --
benzothiazol-3(2H)-yl)acetamide 289 41
2-(2-oxo-1,3-benzothiazol-3(2H)- (208) -- yl)acetamide 42
2-(6-chloro-2-oxo-1,3-benzothiazol- 243/ 4.52 (s, 2 H), 7.15 (d, J
= 8.6 Hz, 1 H), 3(2H)-yl)acetamide 245 7.29 (s, 1 H), 7.36 (m, 1
H), 7.68 (s, 1 H), 7.79 (s, 1 H) 43 6-bromo-3-(1H-imidazol-1- 310/
6.15 (s, 2 H), 6.87 (s, 1 H), 7.22 (s, 1 H),
ylmethyl)-1,3-benzothiazol-2(3H)- 312 7.53-7.96 (m, 4H) one 44
6-bromo-3-(2-oxopropyl)-1,3- (285/ -- benzothiazol-2(3H)-one 287)
45 2-(6-nitro-2-oxo-1,3-benzothiazol- 253 -- 3(2H)-yl)acetamide 46
2-(6-bromo-2-oxo-1,3- (300/ 1.5 (d, J = 7.2 Hz, 3 H), 5.17 (q, J =
7.2 Hz, benzothiazol-3(2H)-yl)propanamide 302) 1 H), 7.13 (d, J =
8.9 Hz, 1 H), 7.32 (s, 1 H), 7.51 (dd, J = 8.7 Hz, J = 2.1 Hz, 1
H), 7.59 (s, 1 H), 7.96 (d, J = 2.1 Hz, 1 H) 47
2-(6-bromo-2-oxo-1,3- (300/ 1.5 (d, J = 7.3 Hz, 3 H), 5.17 (q, J =
7.3 Hz, benzothiazol-3(2H)-yl)propanamide 302) 1 H), 7.13 (d, J =
8.7 Hz, 1 H), 7.32 (s, 1 H), 7.51 (dd, J = 8.7 Hz, J = 2.1 Hz, 1
H), 7.58 (s, 1 H), 7.96 (d, J = 2.1 Hz, 1 H) 48
2-(6-fluoro-2-oxo-1,3-benzothiazol- 284 4.55 (s, 2 H), 7.12-7.25
(m, 1 H), 7.32 (s, 1 3(2H)-yl)acetamide H), 7.61-7.69 (m, 2 H),
7.73 (s, 1 H) 49 2-(6-methyl-2-oxo-1,3- (222) 2.28 (s, 3 H), 4.48
(s, 2 H), 7.00 (d, J = 8.2 Hz, benzothiazol-3(2H)-yl)acetamide 1
H), 7.11 (d, J = 8.1 Hz, 1 H), 7.26 (s, 1 H), 7.41 (s, 1 H), 7.67
(s, 1 H) 50 6-fluoro-3-(1H-imidazol-1- 234 6.15 (s, 2 H), 6.98 (s,
1 H), 7.19 (m, 1 H), ylmethyl)-1,3-benzoxazol-2(3H)- 7.35 (s, 1 H),
7.49 (dd, J = 8.5, 2.4 Hz, 1 H), one 7.63 (dd, J = 8.7, 4.6 Hz, 1
H), 7.98 (s, 1 H) 51 1-(1H-imidazol-4- 215 5.11 (s, 1 H), 5.21 (s,
2 H), 6.52 (m, 1 H), ylmethyl)pyrazolo[1,5-a]pyridin- 7.02 (s, 1
H), 7.15 (m, 2 H), 7.56 (s, 1 H), 2(1H)-one 8.48 (d, J = 6.5 Hz, 1
H), 12.02 (m, 1 H). 6-chloro-2-(1H-imidazol-4- 262/ 3.59 (m, 2 H),
4.51 (m, 4 H), 6.95 (s, 1 H), ylmethyl)-1,4-dihydroisoquinolin- 264
7.26 (s, 2 H), 7.32 (s, 1 H), 7.56 (s, 1 H), 3(2H)-one 11.92 (s, 1
H) 52 2-(6-chloro-3-oxo-3,4- 251/ 1.29 (d, J = 7.28 Hz, 3 H), 3.59
(m, 2 H), dihydroisoquinolin-2(1H)- 253 4.44 (s, 2 H), 5.03 (q, J =
7.28 Hz, 1 H), yl)propanamide 7.05 (s, 1 H), 7.31 (m, 4 H) 53
5-chloro-2-(1H-imidazol-4- 262/ 3.60 (s, 2 H), 4.55 (s, 2 H), 4.57
(s, 2 H), ylmethyl)-1,4-dihydroisoquinolin- 264 6.96 (s, 1 H), 7.24
(m, 2 H), 7.38 (d, J = 7.3 Hz, 3(2H)-one 1 H), 7.56 (s, 1 H), 11.9
(m, 1 H) 54 2-(6-chloro-2-oxo-3,4- (238/ 2.58 (m, 2 H), 2.90 (m, 2
H), 4.40 (s, 2 H), dihydroquinolin-1(2H)-yl)acetamide 240) 6.82 (d,
J = 8.5 Hz, 1 H), 7.14 (s (broad), 1 H), 7.24-7.32 (m, 2 H), 7.48
(s (broad), 1 H) 55 2-(6-bromo-2-oxo-3,4- (282/ 2.54 (m, 2 H), 2.86
(m, 2 H), 4.36 (s, 2 H), dihydroquinolin-1(2H)-yl)acetamide 284)
6.74 (d, J = 8.5 Hz, 1 H), 7.11 (s (broad), 1 H), 7.39 (m, 2 H),
7.45 (s (broad), 1 H) 56 1-(1H-imidazol-4-ylmethyl)-3,4- 228 2.66
(m, 2 H), 2.95 (m, 2 H), 5.20 (s, 2 H), dihydroquinolin-2(1H)-one
7.05 (m, 2 H), 7.20 (m, 2 H), 7.52 (s, 1 H), hydrochloride 9.01 (s,
1 H) 57 2-(6-iodo-2-oxo-3,4- (330) 2.53 (m, 2 H), 2.83 (m, 2 H),
4.34 (s, 2 H), dihydroquinolin-1(2H)-yl)acetamide 6.60 (d, J = 8.3
Hz, 1 H), 7.11 (s (broad), 1 H), 7.49 (s (broad), 1 H), 7.50 (m, 1
H), 7.52 (m, 1 H) 58 2-(6-cyano-2-oxo-3,4- (229) 2.76 (m, 2 H),
3.08 (m, 2 H), 4.39 (s, 2 H), dihydroquinolin-1(2H)-yl)acetamide
7.10 (d, J = 9.2 Hz, 1 H), 7.32 (s (broad), 1 H), 7.68 (s (broad),
1 H), 7.84 (m, 2 H) 59 7-chloro-2-{[2- 394/ (CDCl.sub.3): 3.01 (m,
2 H), 3.15 (m, 2 H), (trifluoromethyl)imidazo[1,2- 396 4.36 (s, 2
H), 5.15 (s, 2 H), 6.53 (d, J = 8.32 Hz,
a]pyridin-3-yl]methyl}-1,2,4,5- 1 H), 6.83 (m, 2 H), 6.97 (m, 1 H),
7.27 (m, tetrahydro-3H-2-benzazepin-3-one 1 H), 7.58 (d, J = 9.29
Hz, 1 H), 8.19 (d, J = 6.85 Hz, 1 H) 60 7-chloro-2-(1H-imidazol-4-
276/ 2.87 (m, 2 H), 3.08 (m, 2 H), 4.64 (d, 16.31 Hz,
ylmethyl)-1,2,4,5-tetrahydro-3H-2- 278 4 H), 7.15 (s, 2 H), 7.24
(s, 1 H), 7.46 (s, benzazepin-3-one hydrochloride 1 H), 8.97 (d,
1.00 Hz, 1 H), 14.48 (s, 1 H) 61 7-chloro-3-(1H-imidazol-4- 276/
3.02 (m, 2 H), 3.83 (m, 2 H), 3.92 (s, 2 H),
ylmethyl)-1,3,4,5-tetrahydro-2H-3- 278 4.60 (s, 2 H), 7.20 (m, 3
H), 7.55 (s, 1 H), benzazepin-2-one hydrochloride 9.02 (d, 1.25 Hz,
1 H), 14.57 (s, 1 H) 62 7-chloro-3-{[2- 394/ 2.85 (m, 2 H), 3.61
(m, 2 H), 3.95 (s, 2 H), (trifluoromethyl)imidazo[1,2- 396 5.08 (s,
2 H), 7.06 (m, 2 H), 7.18 (m, 2 H), a]pyridin-3-yl]methyl}-1,3,4,5-
7.46 (m, 1 H), 7.72 (d, J = 9.03 Hz, 1 H),
tetrahydro-2H-3-benzazepin-2-one 8.39 (d, J = 6.78 Hz, 1 H) 63
1-[(5-fluoro-2-phenyl-1H-indol-1- 323 1.53 (m, 4 H), 2.32 (t, J =
6.5 Hz, 2 H), yl)methyl]piperidin-2-one 2.49 (t, J = 6.0 Hz, 2 H),
5.90 (s, 2 H), 6.50 (s, 1 H), 6.97 (td, J = 9.3, 2.5 Hz, 1 H), 7.25
(m, 1 H), 7.49 (m, 6 H) 64 1-[(2-phenyl-1H-indol-1- 305 1.53 (m, 4
H), 2.32 (t, J = 6.5 Hz, 2 H), yl)methyl]piperidin-2-one 2.51 (t, J
= 6.0 Hz, 2 H), 5.94 (s, 2 H), 6.55 (s, 1 H), 7.20 (m, 2 H), 7.46
(m, 5 H), 7.61 (dd, J = 16.3, 7.8 Hz, 2 H) 65
[(2E)-1-(1H-imidazol-4-ylmethyl)-4- 232 0.85 (t, J = 7.3 Hz, 3 H),
1.22 (m, 2 H), propylpyrrolidin-2- 1.34 (m, 2 H), 2.36 (m, 1 H),
2.48 (m, 1 H), ylidene]cyanamide 2.99 (dd, J = 16.8, 8.5 Hz, 1 H),
3.19 (dd, J = 9.8, 7.0 Hz, 1 H), 3.64 (t, J = 9.3 Hz, 1 H), 4.37
(s, 2 H), 7.06 (s, 1 H), 7.60 (s, 1 H), 12.02 (m, 1 H) 66
2-[(2E)-2-(cyanoimino)-4- 209 (CDCl.sub.3): 0.94 (t, J = 7.3 Hz, 3
H), 1.34 (m, 2 propylpyrrolidin-1-yl]acetamide H), 1.49 (m, 2 H),
2.57 (m, 2 H), 3.13 (m, 1 H), 3.39 (dd, J = 10.3, 7.0 Hz, 1 H),
3.79 (dd, J = 10.0, 8.3 Hz, 1 H), 4.06 (s, 2 H), 5.72 (s, 1 H),
6.41 (s, 1 H) 67 2-[(2E)-2-(cyanoimino)-4- 223 (CDCl.sub.3): 0.93
(td, J = 7.3, 3.5 Hz, 3 H), propylpyrrolidin-1-yl]propanamide 1.34
(m, 2 H), 1.44 (m, 5 H), 2.52 (m, 2 H), 3.13 (m, 1 H), 3.28 (ddd, J
= 21.6, 10.3, 6.8 Hz, 1 H), 3.76 (ddd, J = 14.1, 10.3, 8.0 Hz, 1
H), 5.56 (s, 1 H), 4.80 (m, 1 H), 6.41 (m, 1 H) 68
2-[(2E)-2-(cyanoimino)-4- 237 0.94 (m, 6 H), 1.34 (m, 2 H), 1.45
(m, 2 H), propylpyrrolidin-1-yl]butanamide 1.72 (m, 1 H), 1.99 (m,
1 H), 2.51 (m, 2 H), 3.22 (m, 2 H), 3.75 (ddd, J = 54.2, 10.5, 8.0
Hz, 1 H), 4.56 (m, 1 H), 5.55 (s, 1 H), 6.34 (m, 1 H) 69
N-[(2E)-1-(1H-imidazol-4-ylmethyl)- 285 (CD.sub.3OD): 0.91 (t, J =
7.3 Hz, 3 H), 1.32 (m, 4-propylpyrrolidin-2- 2 H), 1.40 (m, 2 H),
2.40 (m, 1 H), 2.65 (dd, ylidene]methanesulfonamide J = 17.6, 7.5
Hz, 1 H), 2.99 (s, 3 H), 3.11 (dd, J = 10.5, 7.0 Hz, 1 H), 3.24
(dd, J = 17.8, 8.5 Hz, 1 H), 3.58 (dd, J = 10.5, 8.0 Hz, 1 H), 4.54
(s, 2 H), 7.11 (s, 1 H), 7.68 (d, J = 0.5 Hz, 1 H)
Example 36
LBS Binding Assay
[0717] [LBS stands for Levetiracetam Binding Site cf. M. Noyer et
al., Eur. J. Pharmacol. (1995), 286, 137-146.]
[0718] The inhibition constant (K.sub.i) of a compound is
determined in competitive binding experiments by measuring the
binding of a single concentration of a radioactive ligand at
equilibrium with various concentrations of the unlabeled test
substance. The concentration of the test substance inhibiting 50%
of the specific binding of the radioligand is called the IC.sub.50.
The equilibrium dissociation constant K.sub.i is proportional to
the IC.sub.50 and is calculated using the equation of Cheng and
Prusoff (Cheng Y. et al., Biochem. Pharmacol. (1972), 22,
3099-3108).
[0719] The concentration range usually encompasses 6 log units with
variable steps (0.3 to 0.5 log). Assays are performed in mono- or
duplicate, each K.sub.i determination is performed on two different
samples of test substance.
[0720] Cerebral cortex from 200-250 g male Sprague-Dawley rats are
homogenised using a Potter S homogeniser (10 strokes at 1,000 rpm;
Braun, Germany) in 20 mmol/l Tris-HCl (pH 7.4), 250 mmol/l sucrose
(buffer A); all operations are performed at 4.degree. C. The
homogenate is centrifuged at 30,000 g for 15 min. The crude
membrane pellet obtained is resuspended in 50 mmol/l Tris-HCl (pH
7.4), (buffer B) and incubated 15 min at 37.degree. C., centrifuged
at 30,000 g for 15 min and washed twice with the same buffer. The
final pellet is resuspended in buffer A at a protein concentration
ranging from 15 to 25 mg/ml and stored in liquid nitrogen.
[0721] Membranes (150-200 .mu.g of protein/assay) are incubated at
4.degree. C. for 120 min in 0.5 ml of a 50 mmol/l Tris-HCl buffer
(pH 7.4) containing 2 mmol/l MgCl.sub.2, 1 to 2 10.sup.-9 mol/l of
[.sup.3H]-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide and
increasing concentrations of the test compound of formula (I). The
non specific binding (NSB) is defined as the residual binding
observed in the presence of a concentration of reference substance
(e.g. 10.sup.-3 mol/l levetiracetam) that binds essentially all the
receptors. Membrane-bound and free radioligands are separated by
rapid filtration through glass fiber filters (equivalent to Whatman
GF/C or GF/B; VEL, Belgium) pre-soaked in 0.1% polyethyleneimine
and 10.sup.-3 mol/l levetiracetam to reduce non specific binding.
Samples and filters are rinsed by at least 6 ml of 50 mmol/l
Tris-HCl (pH 7.4) buffer. The entire filtration procedure does not
exceed 10 seconds per sample. The radioactivity trapped onto the
filters is counted by liquid scintillation in a 13-counter
(Tri-Carb 1900 or TopCount 9206, Camberra Packard, Belgium, or any
other equivalent counter). Data analysis is performed by a
computerized non linear curve fitting method using a set of
equations describing several binding models assuming populations of
independent non-interacting receptors, which obey the law of
mass.
Example 37
Animal Model of Sound-Susceptible Mice
[0722] The objective of this test is to evaluate the anticonvulsant
potency of a compound in sound-susceptible mice, a genetic animal
model with reflex seizures. In this model of primary generalised
epilepsy, seizures are evoked without electrical or chemical
stimulation and the seizure types are, at least in part, similar in
their clinical phenomenology to seizures occurring in man (Loscher
W. & Schmidt D., Epilepsy Res. (1998), 2, 145-181; Buchhalter
J. R., Epilepsia (1993), 34, S31-S41).
[0723] Male or female genetically sound-sensitive mice (14-28 g;
N=10), derived from a DBA strain originally selected by Dr. Lehmann
of the Laboratory of Acoustic Physiology (Paris) and bred in the
UCB Pharma Sector husbandry unit since 1978, are used. The
experimental design consisted of several groups, one group
receiving the vehicle control and the other groups different doses
of the test-compound. The compounds are administered
intraperitoneally 60 minutes before the induction of audiogenic
seizures. The range of the doses administered had a logarithmic
progression, generally between 1.0.times.10.sup.-5 mol/kg and
1.0.times.10.sup.-3 mol/kg, but lower or higher doses are tested if
necessary.
[0724] For testing, the animals are placed in small cages, one
mouse per cage, in a sound-attenuated chamber. After a period of
orientation of 30 seconds, the acoustic stimulus (90 dB, 10-20 kHz)
is delivered for 30 seconds via loudspeakers positioned above each
cage. During this interval, the mice are observed and the presence
of the 3 phases of the seizure activity namely wild running, clonic
and tonic convulsions, is recorded. The proportion of mice
protected against wild running, clonic and tonic convulsions,
respectively, is calculated.
[0725] For active compounds, an ED.sub.50 value, i.e. the dose
producing 50% protection relative to the control group, together
with 95% confidence limits, is calculated using a Probit Analysis
(SAS/STAT.RTM. Software, version 6.09, PROBIT procedure) of the
proportions of protected mice for each of the 3 phases of the
seizure activity.
[0726] Compounds synthesized according to the procedure described
in examples 1 to 33 and described in table 1 are tested in the SV2
binding assay and/or audiogenic seizure in mice, according to the
procedure described above, and are found active.
* * * * *